Gilberto Alves-MS-MRMC

Send Orders for Reprints to [email protected] Mini-Reviews in Medicinal Chemistry, 2017, 17, 000-000

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REVIEW ARTICLE

Recent Highlights on Molecular Hybrids Potentially Useful in Central Nervous System Disorders Mariana Matias1,2, Samuel Silvestre1,2, Amílcar Falcão2,3 and Gilberto Alves1,2* 1

CICS-UBI – Health Sciences Research Centre, University of Beira Interior, Rua Marquês d’Ávila e Bolama, 6201-001 Covilhã, Portugal; 2CNC – Centre for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; 3Pharmacology Department, Faculty of Pharmacy, University of Coimbra, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal

ARTICLE HISTORY Received: January 02, 2016 Revised: May 26, 2016 Accepted: October 06, 2016 DOI: 10.2174/13895575176661611111101 21

Abstract: Molecular hybridization is a recent strategy based on the covalent fusion of two or more pharmacophores to create a single molecule with multiple mechanisms of action, which represents an encouraging approach in the development of new drugs with potential therapeutic application in several pathologies. This review provides a comprehensive perspective of the most relevant advances in the development of hybrid molecules acting in the central nervous system. For instance, several opioid hybrids based on endogenous opioid peptides (e.g. enkephalins, deltorphins and endomorphins) have been developed, and γ-aminobutyric acid (GABA) agonists have also been designed for neuropathic pain control. In addition, a number of hybrid compounds have also been synthesized and evaluated for their anticonvulsant activity and neurotoxicity, which may be further developed as potential antiepileptic drugs. Moreover, several hybrid compounds have also been designed for the treatment of neurodegenerative diseases focusing primarily on Alzheimer’s disease by targeting the cholinergic neurotransmission, as acetylcholinesterase inhibitors, and the amyloid β-protein deposition. There are also studies addressing hybrid compounds including an antioxidant moiety, which can be potentially useful in Alzheimer’s and Parkinson’s diseases and other neurodegenerative disorders. Additionally, other research works have also shown promising hybrid molecules for depression, autism and cocaine addiction. Thus, the development of molecular hybrid compounds seems to be a promising strategy in the discovery of novel therapeutic drugs.

Keywords: Alzheimer’s disease, central nervous system, epilepsy, molecular hybridization, pain, Parkinson’s disease. 1. INTRODUCTION Central nervous system (CNS) disorders comprise multiple diseases the symptoms of which range from cognitive impairment to maniac behavior or depression, and they affect millions of people worldwide. In developed countries due to the improvement of living conditions, longer life expectancy and consequent population ageing, the occurrence of CNS diseases is likely to increase in the next years, often accompanied by disability and decline in quality of life [1, 2]. These factors coupled with the diverse mechanisms and heterogeneous pathogenesis of this kind of diseases have emphasized the need to develop new and more effective therapies [3-5]. Most of the current single-target directed drugs have proven to be ineffective to achieve the therapeutic goals [6] and, therefore, novel strategies have *Address correspondence to this author at the Faculty of Health Sciences, University of Beira Interior, CICS-UBI – Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilhã, Portugal; Tel: +351 275 329002; Fax: +351 275 329099; E-mail: [email protected] 1389-5575/17 $58.00+.00

been used to develop new CNS-active drugs based on singlemolecular compounds that simultaneously influence multiple targets (multi-target directed drugs) [7]. These molecular compounds can be produced involving genetic strategies [8, 9], as well as by total or partial chemical synthesis [10]. A recent approach in medicinal chemistry that represents an encouraging research field in the development of new drugs is the design and preparation of molecular hybrids [11]. Hybrid molecules are constituted by two or more pharmacophores, natural or unnatural, which are covalently linked, forming a single compound capable to have one or multiple pharmacological actions. The combination of structural moieties allows obtaining molecules with potential dual activity, as a result of the union of distinct pharmacophores that can act simultaneously on the same or different pharmacological targets [12-15]. Indeed, these pharmacological agents are proving to be more efficacious, economical and safer than the single-target directed drugs [5, 14]. These molecules are usually classified in three different categories (A, B and C); the category A concerns a single © 2017 Bentham Science Publishers

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target and both entities of the hybrid molecule are able to interact with the target; in the category B, the two entities of the hybrid molecule act independently on two different and nonrelated targets; and in the category C, both entities of the hybrid molecule act at the same time on two connected targets [14]. Moreover, the design of a hybrid molecule has some restrictions: (i) the molecules must contain two or more pharmacophores that exert biological actions via different binding sites; (ii) to be of clinical value the biological properties must be present in the same concentration range; and (iii) hybrid molecules must be resistant to the metabolic elimination processes, avoiding, after administration, the regeneration of the original drugs [16]. The hybridization approach has been applied in several fields, for example, to destroy microorganisms like bacteria and fungi that are becoming resistant to the common drugs used to treat infections [17-21]. For instance, a major problem concerning the drug resistance is the rapid emergence of multidrug-resistant malarial parasites that can be fatal to humans [22-24]. In this context, hybrid molecules to combat malaria have been synthesized with success and some of them have already been tested in clinical trials [25]. Also, hybridization techniques have been applied in the development of molecules useful against different kinds of cancers such as hormone-dependent breast cancer [26, 27], oropharyngeal, cervical and colorectal cancer [28] and others [29-33]. Some of these compounds have shown potent antiproliferative activities, promoting apoptosis in cancer cells and reducing toxicity against normal cells [34-36]. The design of hybrid molecules as potential cardiovascular drugs is also under development, for instance, to control hypertension and cardiovascular impairment and to prevent oxidative vascular damage [37]. Other research areas employing hybridization strategies include diabetes [38-40], cystic fibrosis [41], inflammation [42-45], chronic obstructive pulmonary disease [46], human immunodeficiency virus [47], gastrointestinal diseases [48], obesity [49], osteoporosis [50] and skin disorders [51]. There are also studies reporting the use of hybrid drugs with multiple biological properties [52], namely, molecules that can act simultaneously against malaria and human immunodeficiency virus [15] or those with antimicrobial and antitumor activities [53-56]. Specifically, this review is focused on and summarizes recent developments on molecular hybrid entities directed to the treatment of CNS-related disorders, in particular in those with interest for pain management, epilepsy, neurodegenerative diseases (e.g., Alzheimer’s disease and Parkinson’s disease) and other disorders. 2. PAIN MANAGEMENT Pain is an unpleasant sensory and emotional experience caused by the conscious awareness of a noxious stimulus. The perception of the intensity of pain is dependent on two pathways: the interactions between nociceptive and nonnociceptive impulses in the ascending system and the activation of the descending pain-inhibitory system [57]. Due to the clinical relevance of pain, great efforts have been invested in the characterization of peripheral and central mechanisms involved in the induction of nociception.

Matias et al.

Furthermore, there is an increasing awareness of the importance of cognitive/affective pain components [58, 59]. Acute and chronic pain can lead to a significant disability with social and economic implications [60]; these types of pain may have a variety of etiologies ranging from tissue injury caused by trauma or chronic diseases to health conditions in which there is no direct evidence of cause (e.g. fibromyalgia) [61]. As pain is always a subjective sensation, its inadequate assessment is frequently identified as one of the most significant barriers to effective pain treatment [62]. The choice of suitable analgesic drugs usually depends on the kind of pain (acute or chronic), intensity, duration of pain stimuli and etiology. Among the clinically available analgesic drugs, opioids are widely used for the management of chronic and acute pain. The clinical usefulness of opioids is, however, hampered by their side effects that can have a negative impact on the patients’ quality of life [63, 64]. Additionally, a diverse group of drugs that are often used for other clinical conditions may also have a great analgesic effectiveness as pain adjuvant therapies. For instance, several tricyclic antidepressants and antiepileptic drugs (AEDs) [65, 66] are widely used for the management of neuropathic pain; indeed, neuropathic pain is a type of chronic pain that leads to damage or other dysfunctions in the central and peripheral nervous systems and it is often refractory to the treatment with opioids, non-steroidal anti-inflammatory drugs and acetaminophen [67, 68]. Hence, due to the lack of satisfactory pharmacotherapeutic options available for chronic pain, this topic has gained an increasing interest in the context of drug research [69]. 2.1. Opioid/Opiate Analgesics The opioid system is the major endogenous pathway capable of modulation of pain signal transmission and perception. In this context, endogenous opioid peptides as enkephalins, endorphins, deltorphins and endomorphins are implicated in a variety of processes in the central and peripheral nervous systems, including the modulation of reward, pain and emotion [70]. The biological activities of these opioid peptides are mediated through three major opioid receptor types (µ, δ and κ) and the distinct molecular structure of these peptides has an impact on their selectivity for the different receptors and consequently on their activity profile [71, 72]. However, the clinical utility of naturally occurring opioid peptides is limited because of their poor bioavailability, susceptibility to enzymatic degradation and incapacity to penetrate the blood-brain barrier (BBB) [73, 74]. A promising approach to obtain a selective agonist by adopting a different conformation and increasing the enzymatic stability and activity can be the cyclization of linear active peptides. An example of this strategy was represented in a study by Ciszewska et al. [72] which investigated diverse cyclic opioid structures with different ring sizes. These peptides were evaluated in the µ receptorrepresentative guinea-pig ileum and δ receptor-representative mouse vas deferens assays, and it was shown that the hybridization through the extension of the enkephalin sequence at its C-terminus by a deltorphin fragment (Fig. 1) [75, 76] resulted in molecules with different receptor

Highlights on Molecular Hybrids for CNS Disorders


selectivity, favoring the interaction with the δ receptor and decreasing the affinity for µ receptor. Among the studied structures, the most active was peptide 1 (Fig. 1), in which an 18-membered ring was formed by incorporation of sidechain amino groups of D-lysine and diaminopimelic acid [72]. OH

H2N

N H

O

Other endogenous opioids largely studied are endomorphins 1 and 2 (Fig. 2) because they are highly potent and selective µ-opioid receptor agonist neuropeptides [77, 78]. Considering the fact that substance P (Fig. 2) is capable of intensifying opioid-mediated analgesia in low doses, Varamini et al. [79] conjugated the N-terminal amino acids of endomorphin-1 with the C-terminal fragments of substance P. A lipoamino acid was also attached to the Nterminal of endomorphin-1/substance P hybrid peptides to enhance their resistance against enzymatic hydrolysis and lipophilicity, consequently improving the passive diffusion of the peptides across biological membranes such as the BBB. In this study, the metabolic stability and membrane permeability were evaluated using the Caco-2 cell line. Among the compounds evaluated, structure 2 (Fig. 2) showed a relatively high µ-opioid receptor binding affinity and selectivity, and an improved membrane permeability and metabolic stability when compared with the parent peptides. In other research work, Mollica and co-workers [80] linked the endogenous opioid endomorphin-2 with a synthetic opioid peptide DAMGO (Fig. 2), being both structural moieties selective for the µ receptors. In this study, compound 3 (Fig. 2) with two N-methyl residues had the highest affinity and selectivity toward the µ-opioid receptors (in vitro receptor binding assay), a relevant activity in the µ receptor-representative guinea-pig ileum bioassay and also revealed to be the most potent structure in antinociceptive tests. This study confirmed that N-methylation is not only related with a relevant metabolic stability but it is also significantly associated with the bioactive conformation of endomorphine-2 analogues and with their interaction with the µ-opioid receptors.

S

O

H N

O

H N

OH

N H

O

O

Met-enkephalin

OH O

H N

H2N O

CH3

O

H N

N H

O

O

H N

N H

O

O

NH2

N H

O

OH Deltorphin I

OH O

H N

H2N

N H m NH

O O

N H

H N

m= 4

O HN

O H N

O

O

O

H N

N H

H N

N H

O

3

NH2 O

1

Fig. (1). Chemical structures of the analgesic peptide 1 and the endogenous opioids met-enkephalin and deltorphin I [72, 75, 76].

Another research work involved the synthesis of new hybrid molecules incorporating the fentanyl skeleton and a guanidine moiety from agmatine (Fig. 3) linked through an

NH HO

HO

HN

NH2 N O

NH

HN

NH2

NH2

N

O O

O

O

NH2

O O

NH O Endomorphin-2

Endomorphin-1

Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 Substance P

HO

NH2 O

H N

O

O N H

N O

OH

N H

DAMGO

H2N HO

NH

C8H17

O

HN

NH N O

NH O 2

O O

HO NH Phe-Gly-Leu-Met-NH2

Bn

NH2 N O

N

N O O

NH OH

O 3

Fig. (2). Chemical structures of compounds 2 and 3 (endomorphine-1 and endomorphine-2 analogs, respectively) and their precursors [7880].

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alkyl or an aromatic spacer [81]. This molecule series was developed based on the fact that fentanyl is a potent µ-opioid receptor agonist frequently used in the treatment of moderate to severe pain [82] and some evidence suggests that agmatine attenuates neuropathic pain in rats [83]. This study revealed that the presence of the guanidine and the Nphenethyl piperidyl propanamide core was necessary for these hybrid compounds to bind to I2-imidazoline binding site and µ-opioid receptors, both involved in analgesia mechanisms. Compound 4 (Fig. 3), which has six methylene units linking the two pharmacophores, showed to be a good µ-opioid agonist in binding studies; however, in in vivo assays, it did not produce significant analgesia [81].

O H N

N H2N N

NH2 NH

antiallodynic and antihyperalgesic activities. In this study, it was observed that compound 5a (Fig. 4) was the most active in the maximal electroshock seizure (MES) model and in the subcutaneous pentylenetetrazol (scPTZ) test, and revealed no neurotoxicity in the rotarod test. Compounds were also evaluated in two acute nociceptive mouse models, the acetic acid-induced writhing test and the formalin test. In these assays compound 5b (Fig. 4) was the most potent, leading to a 99% inhibition in acetic acid-induced writhing test. In the formalin test the most active chemical entities were the compounds 5c [for phase 1 (0-5 min), with 75% inhibition] and 5d [for phase 2 (10-30 min), with 80% inhibition] (Fig. 4). To assess the antihyperalgesic and antiallodynic activities two peripheral neuropathic pain models were also used: the chronic constriction injury and the L5 spinal nerve ligation; compound 5d completely reversed the spontaneous pain response in both models. These results suggested that the 5aryl substituted 1,2,4-triazole derivatives were the most interesting compounds due to their antihyperalgesic and antiallodynic properties [84].

Agmatine

Fentanyl

3. EPILEPSY O N

H N 6

NH NH2

N 4

Fig. (3). Chemical structures of fentanyl, agmatine and analgesic compound 4 [81]. OH

H2N

HN O

O

N R2

N

GABA

R1 Cl 5a: R1=

5b: R1=

R2= (CH2)3NH2

Br

R2= (CH2)3NH2 O

5c: R1= (CH2)3COOH

R2=

N O

5d: R1= (CH2)3COOH

R2=

Fig. (4). Chemical structure of GABA and examples of compounds studied for the control of neuropathic pain [84].

2.2. Analgesic Adjuvant Therapy One of the most important approaches to control chronic neuropathic pain involves the activation of γ-aminobutyric acid (GABA) (Fig. 4) mediated inhibitory neuronal pathways. Thus, as 1,2,4-triazole derivatives also showed antinociceptive activity, Yogeeswari et al. [84] synthesized GABA derivatives including the 1,2,4-triazol-2H-one nucleus and evaluated their anticonvulsant, peripheral analgesic,

Epilepsy is one of the most common serious neurological disorders [85] and affects approximately 50 million people worldwide [86, 87]. This disorder is characterized by recurrent seizures of cerebral origin, presenting episodes of sensory, motor or autonomic phenomena with or without loss of consciousness. The etiology of seizures is complex and remains uncertain and they can be caused by any type of brain pathology [88] or by oxidative injury [89]. Seizures may also arise by a consequence of interactions between predisposing genetic disturbances and pathological-induced changes [88]. The two most important neurotransmitters involved in the regulation of brain neuronal activity are glutamate (an excitatory neurotransmitter) and GABA (an inhibitory neurotransmitter). In fact, changes in the ratio of concentrations/activities of these neurotransmitters can either contribute to increase or decrease the propensity for seizures [90]. In this context, it has been documented that the reduction of GABAergic neuronal activity plays an important role in a number of neurological disorders, including epilepsy [91-93]. Unfortunately, brain GABA levels cannot be efficiently increased by peripheral administration of exogenous GABA because it does not cross the BBB due to its high hydrophilicity. However, other therapeutic strategies have been explored to potentiate the GABAergic neurotransmission; for instance, some of the currently available AEDs promote GABAergic neurotransmission through different ways such as the inhibition of GABA reuptake (e.g. tiagabine), the inhibition of GABA-transaminase (e.g. vigabatrin) and the allosteric modulation of GABA receptors (e.g. stiripentol) [94]. In fact, one approach used for the development of new AED candidates is based on the mechanism of action, making possible the development of GABA-mimetic drugs [95]. Several studies have also been performed focusing on glycine derivatives with potential anticonvulsant activity by interfering with glutamate levels [96, 97]. Moreover, the ion channels also have a critical role in the function of the CNS, where they are involved in the


generation and conduction of nerve impulses by asserting control over the voltage potential across the plasma membrane [98]. Actually, voltage-gated sodium channels have been the molecular targets for several important commonly used drug classes, including hydantoin-related AEDs [99, 100]. Therefore, several studies involving the use of the phenytoin pharmacophore to prepare more potent hydantoin compounds, with less side effects and higher potency for inactivated sodium channels have been published [101, 102]. Over the years, great efforts have been made in the development of clinically effective drugs for the management of epileptic seizures. As previously stated, AEDs are used not only in the treatment of epilepsy but also in other clinical conditions such as analgesic adjuvant therapy. However, this group of drugs is highly susceptible to clinically significant drug-drug interactions [103], and is also associated with undesirable side-effects that can be life threatening [104]. In addition, 30% of the patients with epilepsy continue to have seizures despite the use of appropriately selected AEDs [105]. In view of these facts, there is a clear need to continue developing new AEDs with greater efficacy, namely against pharmacoresistant epilepsy, and/or improved tolerability profiles [101, 106, 107]. Hence, in this section several molecules developed through hybridization strategies are highlighted, which are divided according to the most studied pharmacophores including some of those found in drugs currently used in the clinical practice. 3.1. GABA Hybrids Riluzole (Fig. 5) [108], a functionalized benzothiazole derivative, is an inhibitor of sodium channels and it also inhibits the glutamate release, displaying anticonvulsant and neuroprotective properties [109]. Considering the relevance of this structural moiety, a study reported the incorporation of GABA-like pharmacophores on the benzothiazole nucleus to develop new molecules with synergistic anticonvulsant effects. Among the compounds prepared, the most promising was the N-(6-methoxybenzothiazol-2-yl)-4-oxo-4-phenylbutanamide, 6 (Fig. 5) with the median toxic dose (TD50) of 347.6 mg/kg, and with the median effective doses (ED50) of 40.96 mg/kg and 85.16 mg/kg in the MES and scPTZ tests, respectively. In addition, neither relevant hepatotoxic nor significant CNS depressive effects were observed with this compound [108]. Other studies have demonstrated the promising anticonvulsant activity exhibited by several phthalimide derivatives [110]. In this context, a relevant example was the work carried out by Ragavendran et al. [111], in which amide and acid hydrazone derivatives of phthalimido-GABA were developed by combining the pharmacophoric features of phthalimide, GABA and anilide, and phthalimide, GABA and hydrazones, respectively. Then, the anticonvulsant activity/potency of these two groups of hybrid compounds was evaluated in the MES, scPTZ, subcutaneous strychnine and intraperitoneal picrotoxin-induced seizure threshold tests, and their acute neurotoxicity was assessed through the rotarod assay. Based on the observed results, the authors found that phthalimide-GABA-anilide hybrids were more


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effective than the corresponding phthalimide-GABAhydrazone hybrids, and the compound 7 (Fig. 5) evidenced the most potent anticonvulsant activity [111]. In another research study, supported by the fact that ameltolide (Fig. 5) [112] possesses potent anticonvulsant properties [113], a series of ameltolide-GABA-amides hybrids were developed and synthesized. In this series, the most potent derivative was the compound 8 (Fig. 5), which showed to be active in MES, subcutaneous strychnine and intraperitoneal picrotoxin-induced seizure threshold tests; moreover, at the anticonvulsant dose no neurotoxicity was evidenced when a direct comparison of doses with the standard AEDs was performed. Nevertheless, in these circumstances, a more reliable comparison between the compounds shall be performed using the respective protective index (TD50/ED50) instead of making a direct comparison of doses. Anyway, such as intended, the compounds synthesized had an increased lipophilicity when compared with the GABA and their pharmacological activity profiles suggest their BBB penetration [114].

F

F

O

O

S

F

N

N H

NH2 H2N

Ameltolide

Riluzole

O

O

H N O

S

H N

N

N

O

O

O

6

7

H N O

H N

N H

O 8

Fig. (5). Chemical structure of GABA hybrids and their precursors as well as riluzole and ameltolide [108, 111, 112, 114].

3.2. Benzodiazepine Hybrids Benzodiazepines (e.g. diazepam, Fig. 6) are widely used for CNS disorders, having different and varied therapeutic applications including sedation, sleep induction, reduction of anxiety and anticonvulsant effect [115]. The anticonvulsant activity of several benzodiazepines has been related with their high affinity binding to an accessory site (the “benzodiazepine binding site”) on the GABAA receptor chloride ionophore complex, thus facilitating GABA binding and enhancing the GABAergic neurotransmission and, therefore, limiting the sustained repetitive depolarization of the involved neurons [116, 117]. As the thiazolidine ring has also been associated with anticonvulsant properties, a combination of this nucleus and 1,5-benzodiazepines using molecular hybridization has been reported [118]. Hence, several compounds were synthesized and their anticonvulsant activity was evaluated against MES and isoniazid hydrazone induced seizures, whereas the impairment of motor activity was assessed using an actophotometer and a rotarod

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apparatus. In this series, compounds 9a and 9b (Fig. 6) evidenced the highest anticonvulsant activity. From the pharmacological data obtained it was concluded that small polar and electron rich groups in the phenyl ring directly bound to the benzodiazepine nucleus significantly contribute to the anticonvulsant activity. In addition, these compounds also showed interesting neuroprotective effects [118].

Cl

R

O

N

effective AEDs, Tripathi et al. [123] designed and synthesized a novel group of compounds combining aryl thiosemicarbazides with 4-(aryloxy)phenyl semicarbazones (Fig. 7). The most active compounds in this group were 10a that presented 100% protection in the 6 Hz test (a psychomotor seizure test), and 10b (Fig. 7) that exhibited anticonvulsant activity in both MES and 6 Hz tests. None of the compounds showed neurotoxicity at the highest administered dose (300 mg/kg). Taking into account these findings, it can be concluded that the introduction of halogens in the aryl ring appears to generate more active anticonvulsant compounds than the corresponding unsubstituted derivatives. Docking study results also suggested that these compounds exhibited good binding properties to the glutamate, GABAA delta and GABAA alpha-1 receptors [123]. Pandeya and co-workers [124] also linked semicarbazones with an isatin pharmacophore (Fig. 7) whose anticonvulsant activity has been studied [125]. All hybrids were evaluated in vivo by MES, scPTZ and subcutaneous strychnine and the most active compounds were examined for oral activity in rats at a dose of 30 mg/kg. Within this group, compound 11 (Fig. 7) exhibited interesting anticonvulsant activity in the MES test, with 50% protection at 0.5 h post dose and 100% protection after 2 h, without evidence of neurotoxicity [124]. This hybrid possesses a chlorine, which was associated to an improvement of the anticonvulsant activity when compared with other compounds without this substituent. More recently, Kumar et al. [126] synthesized 5,7-dibromoisatin semicarbazones and compounds 12a, 12b and 12c (Fig. 7) revealed a significant anticonvulsant activity (12a showed protection at the dose of 100 mg/kg at 4 h and compounds 12b and 12c showed activity at the dose of 30 mg/kg at 0.5 h in MES test). These hybrids were also tested for their CNS depressant effects by Porsolt’s force swim pool test and

H N

N

S N

N

O

NH

H N

Diazepam O

S 9a: R= 2-OH 9b: R= 4-(OCH3)

Fig. (6). Chemical structures of diazepam and some thiazolidinebenzodiazepine hybrids [115, 118].

3.3. Semicarbazones Hybrids Aryl thiosemicarbazides (Fig. 7) are a new class of compounds with reported anticonvulsant activity. These compounds do not contain the dicarboxamide group in their molecular structure, which is associated with toxic effects and is found in conventional AEDs such as barbiturates, oxazolidinones and phenytoin [119]. In addition, the structurally related semicarbazones also display interesting anticonvulsant activity [120-122]. In the search for more H N

R

H N

NH2

O O

N

Ar

O N H

O

S

4-(Aryloxy)phenyl semicarbazones

Aryl thiosemicarbazide

H N

R1

H N

H2N

H N

Isatin

H N

O O

N

N NH

S

R2

10a: R1= F 10b: R1= Br

Br

O N H

Cl R2= Cl R2 = Br

11

Br O Br R2 R1

N

O

NH NH

N O

N

N H

N H

N

H N

O

R3 13

12a: R1= Cl 12b: R1= F 12c: R1= F

R2= H R2= Cl R2= Cl

R3= H R3= H R3= CH3

Fig. (7). Chemical structures of the hybrids synthesized containing the semicarbazone moiety [123, 124, 126, 127].



exhibited respectively an increase of 29.05, 51.24 and 32.95% in the immobility time. Similarly to a previous study, compound 12a with a p-chloro in its structure was found to be the most active entity in the CNS depression study [126]. Another research work presented a series of substituted N-(3-methylpyridin-2-yl) semicarbazones [127] and the compounds with a pyridine ring also possess anticonvulsant activity [128]. Among the compounds synthesized, compound 13 (Fig. 7) exhibited anticonvulsant protection after 0.5 h in the MES test (100 mg/kg), and in the subcutaneous strychnine-induced seizure model after 0.5 h and 4 h (100 mg/kg), and at 300 mg/kg in the subcutaneous picrotoxin seizure threshold test after 0.5 h and 4 h, without apparent neurotoxicity at the anticonvulsant doses [127]. 3.4. Pyrrolidone Hybrids The pyrrolidone nucleus is a cyclic imide system and constitutes the basic pharmacophore of several AEDs (e.g., levetiracetam and ethosuximide, Fig. 8). Taking this into account, the combination of this pharmacophore with a pyridine ring was described by Siddiqui et al. [129] aiming the development of new hybrid drugs. In this study, compounds 14a and 14b (Fig. 8) demonstrated comparable anticonvulsant activity to the standard drugs, with ED50 values of 13.4 and 18.6 mg/kg in the MES test and ED50 values of 86.1 and 271.6 mg/kg in the scPTZ test, respectively. None of these compounds exhibited any evidence of neurotoxicity and hepatotoxicity. Accordingly to the information discussed above for compounds 10a, 11, 12a, 12b and 12c, which also contain chloro atoms in their structure, it is not surprising that the structure-activity relationship studies conducted with pyrrolidone hybrids have also evidenced that compounds with a chlorinated substituent at fourth position of the pyridyl moiety are associated to a higher potency [129]. O

R1

N H2N O Levetiracetam

N

O N

O

R2

CN OH

HN

O O

Ethosuximide

14a: R1= Cl 14b: R1= NO2

R2= Cl R2= H

Fig. (8). Chemical structures of levetiracetam and ethosuximide containing pyrrolidone nucleus and pyridinyl-pyrrolidone hybrids [129].

3.5. Quinazolin-4(3H)-one Hybrids The discovery of methaqualone (Fig. 9) represented a relevant landmark in the field of synthetic anticonvulsant agents [130]. This compound contains the quinazolin-4(3H)one nucleus, a heterocyclic ring that is important for its anticonvulsant activity [131, 132]. In this context, using the

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molecular hybridization strategy, Kumar et al. [133] prepared several molecules combining quinazolin-4-(3H)one (Fig. 9) with 4-(aryloxy)phenyl semicarbazones (Fig. 7) because in previous studies the (aryloxy)aryl semicarbazones showed evidence of anticonvulsant activity [134, 135]. Of the prepared hybrids, the most active was compound 15 (Fig. 9), which showed 100% protection in the 6 Hz test at the dose of 100 mg/kg and no neurotoxicity at the highest administered dose (300 mg/kg). Structure-activity studies evidenced, for example, that the methyl substituent at the position 2 of the quinazolin-4(3H)-one nucleus in methaqualone can be replaced by a n-propyl or even a phenyl group, also leading to more active CNS agents. As the previously described hybrids 10a and 10b (Fig. 7), docking studies also predicted that these compounds exhibited good binding properties with glutamate, GABA A delta and GABA A alpha-1 receptors [133]. In addition, the benzothiazole moiety was also incorporated in the quinazolin-4(3H)-one nucleus to obtain single molecules with dual activity. In this series, 16a (Fig. 9) showed significant anticonvulsant activity against the tonic extensor component in the MES test and 16b (Fig. 9) showed activity against the clonic phase of scPTZ-induced seizures. None of these compounds demonstrated any evidence of neurotoxicity or hepatotoxicity [136]. In another study, Malik and co-workers [137] designed and synthesized different molecules also linking the quinazolin-4(3H)-one nucleus and the benzothiazole moiety. The most potent compounds in this group were 17a and 17b (Fig. 9), having significant anticonvulsant potential and minimal toxicity compared to the standard drugs (phenytoin and ethosuximide) in the MES and scPTZ tests and rotarod assay after oral administration in rats at the doses of 30 mg/kg and 50 mg/kg, respectively. In fact, there is evidence that these compounds have slow but sustained absorption and prolonged duration of action. In the scPTZ test, compound 17b displayed an ED50 value of 510.5 µmol/kg and a TD50>2150 µmol/kg, thus determining a very promising protective index (TD50/ED50 >4.2) in comparison to that found with the standard drug ethosuximide (TD50/ED50 >3.0). On the other hand, in the 6-Hz screen test compound 17a revealed to be more active than 17b. Both compounds possess the unsubstituted quinazoline ring that seems to be favorable for their anticonvulsant potential. The presence of electron withdrawing groups like chloro (17a) and trifluoromethoxy (17b) on the benzothiazole ring is associated with a significant anticonvulsant activity and minimal toxicity when compared to reference drugs. These results are probably due to the involvement of GABA pathways as the GABA concentration increased in the rat brain at 2 h (92.1 µg/100 mg of tissue) and 7 days (111 µg/100 mg of tissue) after the treatment (compound 17a), and by antagonizing AMPA mediated excitatory neurotransmission as it was proved against AMPA-induced seizures (ED50 = 37.9 µmol/kg for clonic phase and ED50 = 28.5 µmol/kg for tonic phase) (compound 17b). In addition, both compounds did not lead to any significant increase or malfunctioning of hepatic enzymes in comparison with reference drugs [137]. In another recent research work, the quinazolinone nucleus was the basis of the anticonvulsant activity and the introduction of the benzyloxy tetrazole

8


Matias et al. O N N Methaqualone

R O

O N

Cl O

N

Br

S N

N

N

N 16a: R= H 16b: R= OCH3

15

R O

S N

O N H

N N H

S

N

N

O 17a: R= 6-Cl 17b: R= 6-OF3

N

O

O

19

O N N N N X

N

N

N

NH2

18a: X= CO 18b: X= SO2

N N N N

Fig. (9). Chemical structures of methaqualone and hybrid compounds containing the quinazolin-4(3H)-one nucleus [133, 136-138].

moiety as the core fragment synergized this activity. Within these hybrids, compounds 18a, 18b and 19 (Fig. 9) showed a significantly active profile at 0.5 h post-dose against electrically induced seizures in mice treated intraperitoneally with the dose of 30 mg/kg. Compound 18b also showed 100% of anticonvulsant protection in rats submitted to MES test at the same post-dose time point. These interesting activities have been associated not only to the heterocycles but also to the presence of free carbonyl (18a) and sulphonyl groups (18b). An amino fragment at the para-position of the benzene moiety in the compounds 18a and 18b also seems to be relevant. In addition, the 4-pyridinyl analogue 19 established protection against the scPTZ-induced seizures at the maximum dose of 300 mg/kg at 0.5 h, occurring a loss in activity after 4.0 h. All of these compounds seemed to be devoid of neurotoxicity, even at the maximum dose studied [138].

thiosemicarbazide derivative) and 21 (1,3,4-oxadiazole derivative) (Fig. 10) showed the highest protection (80%) in the scPTZ test in the dose of 100 mg/kg, which was equipotent to phenytoin. None of the compounds showed significant neurotoxicity and 20a was found to be devoid of sedative effects [102].

3.6. Phenytoin Hybrids

Neurodegenerative diseases, such as Alzheimer’s, Parkinson’s and Huntington’s diseases and amyotrophic lateral sclerosis, are a group of pathologies characterized by a progressive and specific loss of determined brain cell populations [142]. The incidence of these diseases increase with ageing, affecting thereby more and more people worldwide [143]. These diseases lead to a considerable deterioration of the patients’ quality of life, having a high socio-economic impact and therefore represent enormous challenges to the scientific community [144]. Alzheimer’s and Parkinson’s diseases are the main neurodegenerative disorders addressed in this review because their high

Phenytoin (Fig. 10), a classic drug commonly used to control epilepsy, has been frequently considered as a starting point for the development of several new anticonvulsant drugs [139]. Using the hybridization approach, phenytoin was combined with several structural moieties associated with anticonvulsant properties such as thiosemicarbazide, 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole rings. Among the synthesized compounds, only the phenyl substituted thiosemicarbazide derivative 20a (Fig. 10) revealed an anticonvulsant protection superior to phenytoin in the MES test at the dose of 30 mg/kg. Compounds 20b (a

A combined phenytoin-lidocaine structure was also developed as a novel sodium channel inhibitor [140], because both parent drugs inhibit the voltage-gated sodium channels that are involved in the pharmacological mechanisms to treat CNS-related disorders such as epilepsy, chronic pain and autism [141]. The compound 22 (Fig. 10) was considered to be the best phenytoin derivative, which presented a value of 71 ± 0.30% of inhibition in the [3H]-Batrachotoxin-B test [140]. 4. NEURODEGENERATIVE DISEASES



9

O O

NH N

HN

N H

O

Lidocaine

Phenytoin

O O

O

O N

HN O

N H

H N

NHR S

N N

N

SH

NH C7H15

O

HN

20a: R= C6H5 20b: R= 4-OCH3C6H4

HN

O O

N H

O 21

N

22

Fig. (10). Chemical structures of phenytoin, lidocaine and some of their hybrids [102, 140].

incidence justifies an urgent need to find effective therapies to control them. However, after the following two sections, hybrid compounds that were designed to combat neurodegenerative diseases in general are also presented, which target basic pathological mechanisms underlying all of them (e.g. oxidative stress). 4.1. Alzheimer’s Disease Alzheimer’s disease (AD) is the most common agerelated neurodegenerative disorder and is characterized by progressive memory loss, language impairment, personality changes and decline in intellectual ability, which worsens as it progresses and eventually leads to death [145, 146]. The complex and multifaceted pathophysiology of this disease, which involves numerous pathways, hinders the development of satisfactory therapies. The etiology of AD includes deficiency in cholinergic neurotransmission, abnormal extracellular accumulation of amyloid β-protein (Aβ), changes in other neurotransmitter systems such as glutamatergic, serotonergic and dopaminergic neurons, and also the involvement of inflammatory, oxidative and hormonal pathways among others [147-149]. Up to date, an effective treatment to prevent the progression of AD is still unknown and the currently approved drugs such as acetylcholinesterase (AChE) inhibitors (tacrine, donepezil, rivastigmine and galantamine) and the N-methyl-D-aspartate (NMDA) antagonist memantine only seem to act as palliative therapeutic approaches to temporary ameliorating the cognitive impairment [146, 150]. The complexity and multiple etiologies of AD can explain the difficulty to obtain desirable therapeutic outcomes with single-target therapeutic strategies, which makes the choice of molecules with dual mechanistic activity one approach potentially more effective [150]. One of these strategies is the molecular hybridization that has been explored mainly using the tacrine pharmacophore to develop new drug candidates able to prevent and stop this neurodegenerative disease. In this review are presented several series of hybrids grouped according to the drugs that are currently being used to manage AD (e.g. tacrine and donepezil) and other important natural and synthetic pharmacophores.

4.2. Tacrine Hybrids Tacrine (Fig. 11) was the first approved cholinesterase inhibitor by the Food and Drug Administration (FDA) for the treatment of AD and it reversibly inhibits this enzyme. Despite its side effects (e.g. hepatotoxicity, gastrointestinal disturbances and hypotension), the search of tacrine-related compounds such as dimmers and hybrids is still of high interest because this compound is the most potent AChE inhibitor in clinical use [151-154]. One example is the combination of tacrine and donepezil, which will be discussed in the next section. Other recent example is the arrangement of methylenedioxybenzene or di- or trimethoxybenzene moieties with tacrine using a long chain linker [155]. This research work was based on the knowledge of the pharmacological properties of tacrine as well as on the fact that compounds containing a methylenedioxybenzene moiety revealed significant activity in inhibiting the selfinduced Aβ aggregation and the AChE enzyme. Within these developed structures, it was observed that compound 23a (Fig. 12), having a methylenedioxybenzene group and an eight-methylene chain linking the two aromatic units, was the most potent AChE inhibitor (IC50 = 7.98 ± 0.12 nM). Compound 23b (Fig. 12), with a trimethoxy substituted benzene moiety and six methylenic linker, exhibited the strongest butyrylcholinesterase (BuChE) inhibition (IC50 = 2.59 ± 0.14 nM); this compound (23b) has three methoxy groups on benzene ring, which seem to be important to BuChE inhibition. Compounds 23c and 23d (Fig. 12) were the most potent inhibitors of the self-mediated aggregation of Aβ42, the most amyloidogenic form of amyloid protein produced in the brain of patients with AD (67.13 ± 5.57% and 68.49 ± 3.63%, respectively) [155]. Considering that oxoisoaporphine synthetic derivatives have shown high AChE inhibitory activity and higher selectivity for AChE over BuChE [156], the combination of these compounds with tacrine was also evaluated. Within this group of compounds, it was found that the heterodimer 24a (Fig. 13) exhibited an interesting AChE inhibitory activity (IC50 = 3.4 ± 0.2 nM) when compared with tacrine, and compound 24b (Fig. 13) showed the highest BuChE inhibition (IC50 = 21.1 ± 1.0 nM). All the compounds in this series revealed a good inhibitory potency on the self-induced

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Matias et al.

Aβ aggregation, and the derivative 24c (85.8 ± 2.2%) was the most active (Fig. 13). Compound 24a also showed to be potent as inhibitor of the AChE-induced Aβ aggregation (83.3 ± 1.2%). The capacity of the compounds to enter the CNS was also assessed using a parallel artificial membrane permeability assay for the BBB (PAMPA-BBB) and it was estimated that compound 24b could cross the BBB while compound 24c had low potential to access the brain [157]. NH2

N Tacrine

Fig. (11). Structure of tacrine [211]. HN

R1

n-2 N H

23a: R1= OCH2O 23b: R1= OCH3 23c: R1= OCH2O 23d: R1= OCH2O

R2 O

N

R2= OCH2O R2= OCH3 R2= OCH2O R2= OCH2O

n= 8 n= 6 n= 6 n= 9

Fig. (12). Structure of tacrine-metoxylated benzene derivatives with anti-Alzheimer activity [155]. N H N N

H N m2

24a: n= 2 m1= 2 m2= 2 24b: n= 2 m1= 3 m2= 3 24c: n= 2 m1= 1 m2= 4

O n

N H

O

m1

Fig. (13). Structure of tacrine-oxoisoaporphine derivatives [157].

Ferulic acid (Fig. 14) is one of the dominant natural phenolic acids and it has shown potent antioxidant properties [158]. Thus, Fang et al. [159] connected the tacrine and the ferulic acid by an alkylenediamine chain aiming to obtain multi-potent anti-Alzheimer drug candidates. In this series, compound 25 (Fig. 14) exhibited the highest inhibitory activity towards both AChE and BuChE, having a reversible and non-competitive inhibitory action for AChE and a reversible but competitive inhibitory action for BuChE. This hybrid also showed relevant antioxidant activity that depends not only on the ferulic acid substructure, but also on the chain length of the connecting linker [159]. The same research group developed a trihybrid based on tacrine-ferulic acid-nitric oxide with potential for the treatment of AD. As compared to the analog lacking the nitrate group, it became evident that the introduction of this group plays a role in the inhibition of electrophorus electricus AChE and equine serum BuChE. In fact, compound 26a (Fig. 14) showed a good inhibition for AChE (IC50 = 3.7 ± 0.6 nM) and BuChE (IC50 = 1.4 ± 0.4 nM) [160]. In addition, the trihybrid 26b (Fig. 14) seems to be very interesting because it can bind to the catalytic (CAS) and peripheral (PAS) sites of the AChE and BuChE enzymes in kinetic studies. This compound exhibited a moderate vasorelaxation in vitro probably due the release of nitric oxide, a better performance in improving

the scopolamine-induced cognition impairment in mice and less hepatotoxicity comparatively to tacrine. However, this compound had no antioxidant activity in the 1,1-diphenyl-2picrylhydrazyl (DPPH) assay, possibly due to the absence of free phenolic hydroxyl groups of the ferulic acid pharmacophore [160]. Additionally, caffeic acid (Fig. 14), an analog of the ferulic acid and a potent antioxidant, also plays an important role in neuroprotection and cytoprotection against oxidative stress [161-163]. Thus, using the hybridization approach, caffeic acid was also bound to tacrine or 6-chlorotacrine and the developed derivatives were biologically evaluated. The compound 27 (Fig. 14) was the most active hybrid as AChE inhibitor, binding to both CAS and PAS of the enzyme. In fact, the chloro-substituted tetrahydroacridine fragment was associated with an increased affinity toward AChE and may also increase the selectivity. These hybrid compounds also exhibited a radical scavenging activity higher than that observed with the individual constituents, as well as interesting inhibitory activities on the self- and AChE-induced Aβ aggregation [164]. Considering that some non-steroidal anti-inflammatory drugs may improve cognition and delay the progression of AD due to their anti-inflammatory and/or antiamyloidogenic activities [165], in some studies tacrinemefenamic acid and tacrine-flurbiprofen hybrids were developed (Fig. 15) [166, 167]. In fact, Bornstein and collaborators [168] by linking tacrine with mefenamic acid obtained an interesting series of compounds with dual activity in the inhibition of CAS and PAS of AChE and the compound 28 (Fig. 15) was the most important of the series with low nanomolar IC50 values under standard conditions (IC50 = 0.418 ± 0.025 nM) and in the presence of reactive oxygen species (ROS)- (IC50 = 0.009 ± 0.003 nM) [168]. In another recent work, a series of trihybrids composed by tacrine, flurbiprofen and nitrate was also prepared as potential therapeutic agent for AD [169]. The results revealed that the length of the alkyl connecting nitrate moiety and the bivalent hybrid (composed by tacrine and flurbiprofen) could significantly influence the AChE inhibitory activity. In fact, it was observed that when the length increases the activity decreases, and a two methylenic spacer was considered to be the optimal length. However, in this study, the most potent compound as AChE inhibitor was the hybrid 29 (Fig. 15), which exhibited an IC50 value (9.1 nM) higher than that observed for tacrine. The kinetic study of cholinesterase inhibition showed that this hybrid compound competes with acetylcholine for the same binding site (CAS) of the enzyme. Additionally, structure 29 afforded a moderate release of nitric oxide and exhibited a moderate blood vessel relaxative activity (28.6%), significant inhibitory effects on the Aβ formation, reducing 17% the levels of Aβ40, and also improved memory impairment in mice. Another important factor favorable to this compound comparatively to tacrine is its better safety profile exhibited in hepatotoxicity assays [170]. In another recent research work, Mao et al. [171] described the design, synthesis and evaluation of a series of o-hydroxyl and o-amino benzylamine-tacrine and o-hydroxy benzylamine-(7-chlorotacrine) hybrids. It was observed that


Mini-Reviews in Medicinal Chemistry, 2017, Vol. 17, No. 0 O

O

O HO

OH

HO

OH

HO Ferulic acid

Caffeic acid

O HN

O

nN

HN

H OH

n= 5

O

N

mN

H O

26a: m= 6 26b: m= 3

O

n ONO

2

O

N

25

HN

11

n= 4 n= 3

OH

nN

H

n= 3

OH N

Cl 27

Fig. (14). Structure of antioxidants ferulic and caffeic acids and their derivatives combined with tacrine [159, 160, 164]. HO

OH

O H N

O

F Mefenamic acid

Flurbiprofen

O

F O HN

H N

nN

O

O HN

H N

H

nN

H

n= 6

n= 7

Cl

ONO2

N

N 28

29

Fig. (15). Structure of non-steroidal anti-inflammatory drugs mefenamic acid and flurbiprofen and their hybrids with tacrine [168, 170].

the structures combining tacrine and substituted o-amino benzaldehyde were better AChE inhibitors than the corresponding hybrids of salicylaldehyde and tacrine. The pharmacological evaluation of these compounds evidenced that the AChE inhibitory potency is closely related to the length of the alkylene chain of the two blocks and the potency generally increases as the number of methylene groups increases. Moreover, the presence of substituted aromatic amino groups also seems to have a favorable effect on the AChE inhibitory activity. Accordingly, from these two series, compound 30a (o-amino benzylamine-tacrine hybrid) (Fig. 16), with a 9-carbon spacer linking the two pharmacophores, exhibited the greatest inhibitory potency towards human AChE (IC50 = 3.52 ± 0.057 nM) and compound 30b (o-hydroxyl benzylamine-tacrine hybrid) (Fig. 16), with an 8-carbon linker, had a good inhibitory potency too; these two derivatives also demonstrated a relevant BuChE inhibitory activity. In contrast to the AChE inhibitory potency, the antioxidant activity of these hybrid compounds decreased as the length of the carbon spacer increased and it was observed that substituted amino groups seem to have an unfavorable effect on the antioxidant properties. Moreover, compounds 30a and 30b had good

inhibitory properties against the Aβ aggregation and also good biometal-chelating ability [171]. R HN

nN H

N 30a: R= N(CH3)2 30b: R= OH

n= 9 n= 8

Fig. (16). Structure of o-amino benzylamine-tacrine and o-hydroxyl benzylamine-tacrine hybrids [171].

Tacripyrines are another relevant class of hybrid structures, which were synthesized from tacrine and nimodipine [172]. The last compound is a drug composed by a 1,4-dihydropyridine moiety that selectively blocks L-type voltage-dependent calcium channels [173, 174]. The nimodipine pharmacophore (Fig. 17) may be important in this context namely because it has been shown that cellular

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Matias et al.

O2N O

O

O

OH

O

O

HN

H N

O

O O

N H

Carvedilol

Nimodipine

R X H N

N R1

S

O

NH2

N H

EtO2C

R2

N H

Phenylthiazole derivative

N

31a: X= CH 31b: X= N

O

H N

S

N H

O

n

N H

N

n= 4

S

nN

H

N

N H

N

N H

N

n= 1 n= 4

N

n= 3

O

H HO

34

N H

n

O

33a: R= H 33b: R= OCH3

N O

R= 4'-OCH3 R= H

H N

N

R

32

HN

N

N H

Cl 35

Fig. (17). Chemical structures of nimodipine, carvedilol and phenylthiazole derivatives and some of their tacrine hybrids [172, 178-180].

calcium dysfunction is also involved in pathogenesis of AD [175-177]. In this study, compound 31a (Fig. 17), one of the most potent hybrids in human AChE inhibition (IC50 = 105 ± 15 nM), was found to be a weak inhibitor of the self-induced Aβ42 aggregation (34.9 ± 5.4%). Molecular modeling studies suggested that the binding of the compound 31a to the AChE PAS mainly involves the R-enantiomer. On the other hand, compound 31b (Fig. 17) was found to be the most potent hybrid as calcium-channel blocker (49% inhibition), whose activity was similar to that obtained with nimodipine. Both compounds were able to cross the BBB and afforded a good degree of neuroprotection when compared to tacrine [172]. Knowing that the phenylthiazole nucleus (Fig. 17) could inhibit tau protein aggregation and may also lead to selfinduced Aβ aggregation blockade, a new series of phenylthiazole–tacrine hybrids was also synthesized. Among them, compound 32 (Fig. 17), with a spacer chain length of ten atoms (no counting N atoms), displayed the highest AChE inhibitory potency binding simultaneously to the CAS and the PAS of AChE, and compound 33a (Fig. 17) showed the highest potency and selectivity for BuChE. In addition, compound 33b (Fig. 17) effectively prevented the selfinduced Aβ42 aggregation, but had no relevant blockage effects on calcium-channels [178]. In another study, the carbazole moiety of carvedilol (Fig. 17), a vasodilating βblocker with antioxidant properties, was linked to the chloro-

substituted tetrahydroacridine moiety of 6-chlorotacrine. Within this group it was observed that compound 34 (Fig. 17), having a three-methylene spacer, showed to be long enough to allow a proper interaction with both sites of the AChE. It also exhibited in vitro inhibitory activity against the self-induced Aβ aggregation (36.0 ± 2.3%) and AChEmediated aggregation (57.7 ± 6.1%). In addition, it revealed a relevant antagonistic effect on the NMDA receptors and was able to protect neuronal cells against the ROS generation evoked by oxidative stress [179]. Additionally, Thiratmatrakul and co-workers [180] also described new tacrine-carbazole hybrids potentially useful as multifunctional anti-Alzheimer agents. Among the compounds synthesized, structure 35 (Fig. 17), with a 5-methylene linker, exhibited the most potent inhibitory activity and selectivity toward electric eel AChE (IC50 = 0.48 ± 0.14 µM) as well as relevant antioxidant activity. The high AChE inhibition produced by this compound was related with its methoxyl group at the 7-position of the carbazole moiety. On the other hand, the presence of this group decreased the BuChE inhibitory activity. Docking studies also indicated that the derivative 35 can bind to both CAS and PAS of the AChE. Furthermore, this compound had a potent antioxidant activity, protecting cell damage against oxidative stress induced by hydrogen peroxide, and had protective effect against Aβ1-42 toxicity in a cell model at the concentration of



100 µM. Moreover, this compound exhibited an ability to improve both short- and long-term memory deficits in mice induced by scopolamine through enhancement of cholinergic signaling [180]. Considering that the benzothiazole moiety is present in compounds that interfere with Aβ peptides [181], Keri et al. [182] conjugated tacrine with this pharmacophore through different suitable linkers. From the pharmacological evaluation studies, compound 36a (Fig. 18), with a five carbon linker, appeared to be the strongest AChE inhibitor with an IC50 value of 0.34 ± 0.1 µM, which is quite similar to the IC50 value obtained for tacrine. Structure-activity studies evidenced that the presence of a simple phenyl group attached to the benzothiazole moiety is associated with the highest inhibitory capacity. Indeed, molecular modeling studies predicted the AChE dual-binding site of this compound (36a). Concerning the self-induced Aβ42 aggregation inhibition, compound 36b (Fig. 18) presented the highest activity (61.3% inhibition). None of these compounds exhibited significant antioxidant activity, possibly because of the absence of phenolic hydroxyl groups [182]. Cl

H N

O

O N H

5

N

X

S

n

N

N N H

8N

H

O N

36a: X= Ph 36b: X= PhCH2

37a: R= Cl 37b: R= H

n= 0 n= 2

R H N

N

H N 9

OH

N 38

Fig. (18). Chemical structures of hybrids synthesized from tacrine and benzothiazole and 5-phenylpyrano[3,2-c]quinoline moieties [182-184].

New hybrid compounds were also developed connecting a 5-phenylpyrano[3,2-c]quinoline moiety with 6-chlorotacrine through an oligomethylene linker containing an amido group at a variable position. The most potent human AChE inhibitor was compound 37a (Fig. 18) with an IC50 value of 7.03 ± 0.3 nM. Molecular modeling and kinetic studies suggested that this compound is able to bind the PAS and the CAS of human AChE. On the other hand, the Aβ antiaggregating effect seems to depend on the position of the amido group within the linker and one of the most potent compounds in the AChE-induced and self-induced Aβ aggregation was compound 37b (45.7 ± 0.3 and 47.3 ± 8.8%, respectively) (Fig. 18). This fact was mainly associated to its two-methylene linker between the amido group and the phenylpirano[3,2-c]quinoline moiety that facilitates the

13

formation of hydrogen bonds with Aβ leading to an increased affinity. This compound was also the most potent β-secretase inhibitor (78% inhibition) and both compounds (37a and 37b) appeared to be able of penetrating the BBB [183]. More recently, the efficacy of a tacrine-8hydroxyquinoline derivative 38 (Fig. 18) was evaluated using in vitro and in vivo models. This compound showed neuroprotective effects in neuronal and astrocytic cell cultures, had anti-amyloid effects in the APP/Ps1 mouse (an AD model), and had also neuroprotective effects in wildtype mice submitted to domoic acid-induced toxicity (an experimental model of neurodegeneration) [184]. A very recent investigational study involved the design and development of tacrine-2,4,5-triphenyl-1H-imidazole hybrids (tacrine-lophine hybrids) as inhibitors of AChE and BuChE. Taking into account all the compounds prepared, the most active as AChE inhibitor was hybrid 39 (IC50 = 5.87 ± 0.3 nM; Fig. 19), which bears an octane chain between the tacrine and lophine moieties (Fig. 19). This result points out that this linker will allow an optimal interaction between the aromatic fragments of the compound and the CAS and PAS of AChE. In addition, it was also observed that a chloride substituent in the para-position of the imidazolic 2-phenyl group is associated with an increased inhibitory activity against BuChE [185]. More studies reported the combination of tacrine with other different natural pharmacophores. Examples of the last compounds include berberine or huprine derivatives that are subsequently discussed. Additionally, the preparation of hybrids linking tacrine derivatives to rhein was also reported [186]. Rhein (Fig. 20) is the main component of rhubarb, a traditional Chinese herb, which has different pharmacological effects such as antioxidant activity and probably positive effects on AD [187]. It has also hepatoprotective effects [188] that can be useful to reduce the above referred liver toxicity caused by tacrine. Among the compounds synthesized, the hybrid 40a (Fig. 20) possessed the most potent inhibitory activity against electric eel AChE (IC50 = 22.0±1.5 nM) and 40b (Fig. 20) showed the highest inhibition against equine serum BuChE (IC50 = 11.0 ± 0.7). On the other hand, compound 40c (Fig. 20) exhibited the strongest inhibition of the AChE-induced Aβ aggregation (70.2% inhibition). Additionally, this last compound showed to be a good metal chelator by effectively chelating Cu2+ and Fe2+ and demonstrated to be safer than tacrine in hepatotoxicity studies [186]. Tacrine was also linked to flavonoids aiming to obtain multi-target molecules against AD (Fig. 20). In this series, structure 41a was the most potent inhibitor for electric eel AChE (IC50 = 8.4 ± 0.8 nM) while 41b showed the strongest inhibition to equine serum BuChE (IC50 = 25.8 ± 0.8 nM). Compound 41c, with a hydroxyl group at the 5position of flavonoid moiety and without the ring at the 2position, was the most potent inhibitor of the Aβ selfinduced aggregation. Structure-activity relationship studies evidenced that an electron-donating group at this position seems to be beneficial to the Aβ self-aggregation inhibitory activity. Compounds 41c and 41d may have metal-chelating ability since they have the 5-hydroxy-4-keto site and, thus, they can serve as metal chelators in treating AD [189].

14


H N

[191] that synthesized a series of new hybrids; among these compounds, structures 44a and 44b (Fig. 22) showed better values than the parent drugs in inhibiting human AChE and BChE and in the AChE-induced Aβ40 aggregation [191].

N

N

HN

N

Matias et al.

n-3

n= 8

N

Lophine

Cl 39

Fig. (19). Structures of lophine and the tacrine-lophine hybrid 39 [185]. OH

O

O

OH HN OH

O

nN

H m

O

R

OH

N

Rhein

HN

O

O

40a: R= Cl 40b: R= H 40c: R= H

n= 6 n= 6 n= 6

m= 2 m= 3 m= 2

O

O

R2

OH

N N

N 41a: R1= OCH3 41b: R1= H 41c: R1= OH 41d: R1= OH

R2= C5H6 R2= C5H6 R2= C5H6 R2 = H

R1

O

Fig. (20). Structures of rhein and hybrids developed from the linkage of tacrine with natural compounds such as rhein and flavonoids [186, 189]. O O O

N Donepezil

Fig. (21). Structure of donepezil [190].

4.3. Donepezil Hybrids Donepezil (Fig. 21) is another drug extensively used in the development of hybrid compounds with potential to treat AD. As indicated above, Alonso et al. [190] described a new series of donepezil-tacrine hybrids, combining tacrine (Fig. 11), 6-chlorotacrine or acridine with the indanone (or phthalimide, a similar group) moiety of donepezil (Fig. 21). Within this series, compounds 42 and 43 (Fig. 22), bearing the phthalimide moiety and a long chain containing respectively ten and nine atoms linking the two heterocyclic systems, exhibited an interesting AChE inhibitory activity (IC50 = 2.8 nM and IC50 = 2.4 nM, respectively) mediated by binding simultaneously to the PAS and CAS of the enzyme [190]. Afterwards, the combination of these two potent molecules was also studied by Camps and collaborators

The compound AP2238 (Fig. 23) was the first published structure designed to bind to both the CAS and PAS of human AChE [192]. Thus, considering its interesting properties, Rizzo et al. [193] described several compounds linking the indanone core of donepezil with the phenyl-Nmethylbenzylamino moiety of AP2238 through a double bond. Instead of the indanone system, an analogous tetralone substituent was also evaluated in this study. An interesting enzyme inhibitory activity was observed when a methoxy group was bound at the position 6 of the tetralone ring, probably because this substituent appeared to be crucial to the interaction of the hybrid compound with the enzyme. The replacement of this methoxy substituent by a pentoxy substituent carrying different amines, e.g. diethylamine (45a) or piperidine 45b (Fig. 23) resulted in a relevant increase in the activity. In fact, both compounds were the most active of this series as AChE inhibitors (IC50 = 0.056 ± 0.003 µM and IC50 = 0.052 ± 0.002 µM, respectively); they also showed a high human BuChE inhibitory activity, but evidenced lower selectivity than donepezil and AP2238. In addition, both compounds 45a and 45b were also able to inhibit the AChEinduced Aβ aggregation (26.4 ± 1.1% and 26.9 ± 3.4%, respectively) and exhibited some degree of inhibitory activity against the self-aggregation of Aβ42 peptide (42.9 ± 0.8% and 48.3 ± 0.9%, respectively), while the reference compounds were completely ineffective [193]. There is also evidence suggesting that the use of monoamine oxidase (MAO) inhibitors might be a valuable approach for the treatment of AD; indeed, MAO inhibitors can lead to a reduction in the formation of neurotoxic products and consequently to a reduction of neuronal damage [194]. Thus, a new strategy appeared combining the benzylpiperidine moiety of donepezil and the indolyl propargylamino moiety of N-[(5-benzyloxy)-1-methyl-1Hindol-2-yl)methyl]-N-methylprop-2-yn-1-amine (Fig. 24), a MAO inhibitor. Among the developed compounds, structure 46a (Fig. 24) was found to be the most promising hybrid revealing to be a potent inhibitor of both MAO-A (IC50 = 5.2 ± 1.1 nM) and MAO-B (IC50 = 43 ± 8.0 nM) and also a moderately potent inhibitor of AChE (IC50 = 0.38 ± 0.05 µM) and BuChE (IC50 = 1.7 ± 0.2 µM). These results pointed out the relevant role played by the 1-benzylpiperidin-4-yl moiety existing in the structure of donepezil and in these hybrids in the AChE inhibition. Moreover, compound 46a was considered a moderate inhibitor of the self-induced Aβ aggregation and prevents the human AChE-induced Aβ aggregation with an inhibitory potency similar to donepezil and significantly higher than tacrine [195]. Additionally, Bautista-Aguilera and co-workers [196] intending to develop donepezil indolyl based amines, amides and carboxylic acid derivatives, linked the N-benzylpiperidine moiety of donepezil with the indole nucleus of compound 46a by a three methylene carbon chain and evaluated their activity in inhibiting the cholinesterase and MAO. In this study, structure 46b (Fig. 24) showed to be a promising drug



O N

N H

N

N H

15

O O N

N

N H

O

N

5

O Cl

43

42

X

O O

N NH

44a: X= O

R= Cl

44b: X= H,H

R= H

R N

Fig. (22). Structures of donepezil-tacrine hybrids [190, 191]. O

O

O

O R (H2C)5 O

O

N

N AP2238

45a: -NEt2 45b:

N

Fig. (23). Structures of the compound AP2238 and the hybrids incorporating donepezil pharmacophore [193]. R N

O

N

N O

N

BnN

N-[(5-benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine

46a: R= CH3 46b: R= H

Fig. (24). Structures of N-[(5-benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine and their hybrids with donepezil [195, 196].

candidate with a potent and selective electrophorus electricus AChE (IC50 = 0.19 ± 0.01 µM) and human MAOA (IC50 = 0.0055 ± 0.0014 µM) inhibition. This compound also displayed moderate equine serum BuChE (IC50 = 0.83 ± 0.16 µM) and human MAO-B (IC50 = 0.15 ± 0.031 µM) inhibitory activities. Docking studies predicted that its linear conformation allows to span both the CAS and PAS site of electrophorus electricus AChE, contributing to its superior binding. It was also observed that the propargylamine group is likely to be an important feature for these derivatives in order to exhibit both AChE- and BuChE-inhibitory activities. For MAO enzymes, molecular modeling studies suggested that the selectivity of compound 46b to MAO-A vs MAO-B is likely to be due to the orientation of their propargylamine and phenyl moieties in the interaction with the enzymes [196]. In another work, new hybrids were designed by combining the N-benzylpiperidine moiety of donepezil with an anti-Alzheimer 2-aminopyridine system, and these two

structural moieties were connected by appropriate polymethylene binding spacers. Among these, compound 47a (Fig. 25), with a hydrogen at the C4 of the pyridine ring, was found to be the most potent and selective hybrid in inhibiting the human AChE (IC50 = 0.0094 ± 0.0004 µM) and BuChE (IC50 = 6.6 ± 0.7 µM). This compound is able to bind simultaneously to the CAS and PAS of AChE and it can also cross the BBB by passive diffusion [197]. The N-benzylpiperidine moiety of donepezil was also linked with 2-chloropyridine heterocyclic ring systems through a polymethylene linker. Within this group, compound 47b (Fig. 25), bearing again a hydrogen at C4, was the most active, being almost equipotent with donepezil as AChE inhibitor (IC50 = 0.013 ± 0.002 µM) and 4-fold less active as BuChE inhibitor (IC50 = 8.13 ± 0.41 µM). Moreover, a permeability study using a BBB-PAMPA assay also indicated that this compound would probably cross the BBB by passive diffusion and docking studies performed suggested that the compound possesses the optimal spacer length that allows a strong interaction with human AChE [198].

16


NC N

O S

R

O

5

NBn

N H NH

47a: n= 3 47b: n= 4

O

R=NH2 R= Cl

49

Fig. (25). Chemical structures of compounds synthesized from Nbenzylpiperidine moiety of donepezil and 2-aminopyridine/2chloropyridine pharmacophores [197, 198].

Fig. (27). Chemical structure of the hybrid 49 constituted by Lglutamic acid, N-benzylpiperidine moiety and a lipophilic α-hexyl ester [202].

Hu et al. [199] also developed a new series of hybrids using a multimethylene linker to connect the dimethoxyindanone unit of donepezil with the hupyridone fragment of huperzine A (Fig. 26); indeed, huperzine A is a novel lycopodium alkaloid that has shown to be a potent, reversible, selective and well-tolerated AChE inhibitor [200, 201]. The diastereomeric mixture (RS,S)-48 (Fig. 26), with a tetramethylene linker, exhibited the strongest AChE inhibition of this series of compounds, having an IC50 value of 9 nM, and no relevant BuChE inhibitory effect was observed [199].

O NH H2N

O

Cl

CN

nN H

BnN

Matias et al.

H N

O

O

In another study, three active groups were joined to Lglutamic acid as a suitable biological linker. The three pharmacophoric groups were a ω-situated N-benzylpiperidine moiety able to bind the CAS of AChE, a N-protecting group capable of interacting with the PAS in order to inhibit Aβ aggregation, and a lipophilic α-hexyl ester important for the crossing of the BBB. The prepared compounds showed good inhibitory activity against human AChE and BuChE, particularly compound 49 (IC50 = 0.10 ± 0.01 µM and IC50 = 0.07 ± 0.01 µM, respectively) (Fig. 27), and were able to bind to the PAS of AChE and consequently inhibit the Aβ fibril formation promoted by this enzyme. The entry in the brain was studied using a PAMPA-BBB assay and the results suggested that the molecules could cross the BBB, probably by passive diffusion. The compounds were also found to be neuroprotectants against both exogenous and mitochondrial ROS [202].

O

O (H2C)4

Huperzine A

NH

48

4.4. Berberine Hybrids

Fig. (26). Chemical structures of huperzine A and its hybrid compound linked to donepezil moiety [199].

Berberine (Fig. 28), a natural isoquinoline alkaloid, has evidenced potential to treat AD [203-205]. Considering that

O

Cl N

O

O O Berberine

OH

O

Br N

O

50a: R=

O

O n

O

n= 4

R 50b: R=

OH

n= 3

O

N

H N

N

O

N

n

O

O

Br

O

S O 51a: n= 3 51b: n= 6

Fig. (28). Chemical structures of berberine hybrids [209, 210].

N

O 52


phenol derivatives as ferulic acid (Fig. 14) and melatonin have a potent antioxidant activity [206-208], Jiang et al. [209] prepared a series of hybrids combining these pharmacophores in the search of multifunctional agents for AD. From all prepared structures, the berberine-pyrocatechol 50a (Fig. 28) was found to be a potent AChE inhibitor (IC50 = 0.123 ± 0.003 µM) and a strong BuChE inhibitor (IC50 = 2.09 ± 0.14 µM) and the hydroquinone berberine hybrid 50b (Fig. 28) presented the highest inhibition of the Aβ aggregation (92%). In an antioxidant activity assay, most of the berberine-benzenediols showed higher activity than berberine-ferulic acid and berberine-melatonin hybrids, probably due to the presence of a phenolic hydroxyl moiety, and compound 50b, possessing a hydroxyl at the paraposition on the benzene ring, had the strongest antioxidant activity (9.54 Trolox equivalents) [209]. Additionally, Huang et al. [210] designed, synthesized and evaluated several berberine-phenyl-benzoheterocyclic and tacrine-phenyl-benzoheterocyclic hybrids as multifunctional anti-Alzheimer agents. Structure-activity relationship studies demonstrated that the potency for AChE inhibition was closely related to the length of the alkylene chain and a 3carbon spacer seem to be the most effective in both series. Accordingly, compound 51a (Fig. 28), combining tacrine and phenyl-benzothiazole linked by a 3-carbon spacer chain, was found to be the most potent AChE inhibitor, with an IC50 value of 0.017 ± 0.002 µM. Hence, it was observed that tacrine-phenyl-benzoheterocyclic hybrids were more potent as AChE inhibitors than berberine-phenyl-benzoheterocyclic hybrids. Compound 51b (Fig. 28) was the most potent as BuChE inhibitor (IC50 = 0.082 ± 0.007 µM). In addition, all the berberine-phenyl-benzoheterocyclic hybrids exhibited greater Aβ42 aggregation inhibitory activities than curcumin and berberine, and within this group the compound 52 (Fig. 28) was the most potent (IC50 = 3.61 ± 0.09 µM) [210]. 4.5. Huprine Hybrids In order to allow the simultaneous interaction with both binding sites of the AChE enzyme, tacrine was connected to huprine Y (Fig. 29), a natural compound with one of the highest affinities for the active site of AChE already reported [211]. Taking into account the data of this study, it was found that the introduction of a protonatable amino group in the linker resulted in an additional increase in the AChE inhibitory activity, probably due to an extra interaction with the AChE gorge as a third recognition site. An unsubstituted tacrine unit 53 (Fig. 29) together with an adequate tether length appeared to have a good inhibitory activity against human AChE. In addition, the presence of a protonatable amino group in the linker seemed to have a detrimental effect on the inhibitory activity of the BuChE, thus explaining the selective effect of these compounds [212]. The series of huprine-tacrine heterodimers continues being explored to find hybrids that have a potential diseasemodifying role in the treatment of AD [213]. Viayna and collaborators [214] attached two pharmacophores belonging to two natural compounds in order to prepare a family of rhein-huprine hybrids. Among others, these authors obtained an interesting racemic hybrid


17

54 (Fig. 29) that was extensively studied. In in vitro assays, it showed to be a potent drug candidate as inhibitor of the human AChE, being the (-)-54 isomer (IC50 = 2.39 ± 0.17 nM) much more potent than the (+)-54 (IC50 = 2930 ± 285 nM). On the other hand, (+)-54 (IC50 = 265 ± 21 nM) was two-fold more potent than (-)-54 (IC50 = 513 ± 58 nM) in inhibiting the BuChE. Contrary to what was observed for the human AChE and BuChE inhibition, in the self-induced Aβ aggregation and β-secretase inhibitory activity (IC50 = 120 ± 90 nM) no significant differences were found between the (+)- and (−)-54 isomers. Ex vivo studies in brain slices of C57bl6 mice conducted with the potential leads (+)- and (−)54 revealed that the compounds efficiently protected against the synaptic failure induced by acute treatments with Aβ42 oligomers. Moreover, they exerted a protective effect on synaptic proteins related with the stability of the synapses and its plasticity in the hippocampus. Additionally, in vivo studies in APP-PS1 transgenic mice treated intraperitoneally for 4 weeks with (+)- and (−)-54 revealed that they were able to reduce the levels of hippocampal total soluble Aβ and to increase the levels of mature amyloid precursor protein [214].

NH2 N Huprine Y

Cl HO O HO

HN HN

O

N

HN HN

8

N

9

O

N Cl 53

Cl 54

Fig. (29). Structures of huprine Y and their analogues [212, 214].

4.6. Choline Hybrids Knowing that phenolic compounds such as caffeic acid (Fig. 14), rosmarinic acid (Fig. 30) and trolox have antioxidant properties, hybrids conjugating the choline group of acetylcholine (Fig. 30) with these antioxidant compounds were also developed. In this group, compound 55, the 3,4dimethoxycinnamic choline ester (Fig. 30), was the strongest AChE inhibitor (IC50 = 7.3 ± 0.8 µM). The rosmarinyl- and trolox-choline derivatives showed a much lower AChE inhibitory activity than that found for caffeic acid analogues, possibly due to the bulkiness and/or the hydroxyl groups of the first two structural groups that may form unfavorable interactions with the enzyme, whereas the methoxy groups in caffeic acid derivatives can form favorable interactions. Regarding antioxidant activity, compound 56 (Fig. 30) appeared to be the strongest antioxidant with an EC50 value

18


Matias et al.

of 4.3 ± 0.2 µM. This fact is probably due to the presence of phenolic hydroxyl groups, which have an important role in the ROS-scavenging action of polyphenols [215]. O HO

O

OH

O

HO

OH

N OH Rosmarinic acid OH

Choline

O HO

O O O

O

N

O

O

N

O

HO OH

56

55

OH

Fig. (30). Chemical structures of phenolic-choline hybrids and their precursors [215].

4.7. Parkinson’s Disease Parkinson’s disease (PD) is the second most common neurodegenerative disorder [216] and it is characterized by loss of dopamine neurons in substantia nigra pars compacta and later in the ventral tegmental area. Possible causes for the neurodegeneration include oxidative stress, misfolded proteins, inflammation, mitochondrial and ubiquitinproteasome dysfunction and impaired protection against potentially harmful substances [217-219]. Some of the symptoms associated with PD involve rigidity, bradykinesia, tremor and postural instability along with cognitive and psychiatric complications [220, 221]. The dopamine precursor L-DOPA (levopoda) has been widely used in the treatment of PD. However, among other disadvantages, the L-DOPA side effects limit its therapeutic use [222]. Over the years, several strategies have been studied to enhance

L-DOPA chemical stability and water or lipid solubility, and also to reduce its susceptibility to enzymatic degradation [223, 224]. For the treatment of PD other options have also been explored such as the use of indirect dopaminergic agents, like selective MAO-B and cathecol-O-methyltransferase inhibitors, and anticholinergic and antiglutamatergic agents [222, 225]. Nevertheless, among the different therapeutic agents developed, direct dopamine agonist therapy still plays an important role in the treatment of this disease. Although the drug therapy of PD seems to be more successful compared to that of AD, the therapeutic approaches currently available do not prevent the degenerative process and consequently the progression of the disease [226]. In this context, D3 receptor appears to be a promising target for the treatment of PD and several therapeutic approaches have been developed towards this dopamine receptor [222]. An example is given by Dutta et al. [227] that, based on the fact that some aminotetralins and disubstituted piperazine derivatives have already demonstrated high selectivity for D3 receptors [228, 229], linked these two pharmacophores as well as some bioisosteric analogues. A preliminary study showed that the length of the linker connecting the aminotetralin moiety with the piperazine fragment plays an important role in the selectivity to D3 receptors. Indeed, a two methylene linker chain was associated with a higher selectivity and potency for the D 3 receptors in comparison with D2 receptors [227]. In a further study by the same research group, several hybrid compounds were also prepared based on the structure of the D3 agonists pramipexole and 7-hydroxy-2-(dipropylamino) tetralin (7OH-DPAT) (Fig. 31) [230]; the results of binding assays indicated that (±)-57 (Fig. 31) has high potency for the D 3 receptor and it was the most selective compound. In addition, the isomer (-)-58 (Fig. 31) presented higher D3 binding potency and selectivity compared to the corresponding (+)-58 isomer. The isomer (-)-58 was also evaluated in vivo in 6hydroxydopamine induced unilaterally lesioned rats and showed high activity and higher duration of action comparatively to apomorphine, the reference compound [231].

N H2N

HO

S

N H Pramipexole

N

N

N 7-OH-DPAT

N

N

H2N S

N

HO

N

57

58 N

N

59a: R=

H2N S

N

N

N R

59b: R=

Fig. (31). Chemical structures of the PD hybrids and their precursors [231, 232].

N

N



The synthesis and evaluation of D3 agonist hybrids with antioxidant activity and potential interest in PD continues to be reported [232]. In addition to D2 and D3 receptors binding assays using HEK-293 cells, the functional activity of some of these compounds in stimulating GTPγS binding was determined in CHO cells expressing human D2 receptors and in AtT-20 cells expressing human D3 receptors. Taking into account the results of all assays, compounds 59a and 59b (Fig. 31) were pointed out as the most interesting hybrids in this work. In fact, compound 59a, an isoquinoline-1-yl derivative, showed a relevant and preferential agonist activity for D3 receptors (Ki = 2.23 nM). In contrast, compound 59b, a quinoline-5-yl derivative, displayed high binding affinity for both D2 and D3 receptors (Ki = 57.7 nM and Ki = 1.21 nM, respectively) despite appreciable selectivity for D3 over D2 receptors. By means of a DPPH radical scavenging assay, these two compounds also exhibited potent and dosedependent radical scavenging activity (IC50 = 45.67 ± 6.89 µM for 59a and IC50 = 39.67 ± 6.23 µM for 59b). Moreover, both compounds showed high activity in two PD animal models, with compound 59b being the most potent in the reserpinized rat model, whereas compound 59a was the most active in the neurotoxin 6-hydroxydopamine induced unilaterally lesioned rat model [232]. 4.8. Other Hybrids for Neurodegenerative Diseases

the

Treatment

of

The oxidative stress is involved in the ageing process and contributes to the pathological changes associated with the initiation and progression of neurodegenerative disorders such as AD, PD, amyotrophic lateral sclerosis and Huntington’s disease [233, 234]. For this reason and as previously referred, several research works have been performed aiming the development of hybrid structures containing antioxidant pharmacophores potentially useful in all these neurodegenerative conditions. A relevant example is the work of Yoo et al. [235] in which a series of cinnamoyl ketoamide hybrids were synthesized combining antioxidants and calpain inhibitors. Calpain is a calciumactivated cysteine protease typically associated with cellular necrosis and, in some neurological disorders, it was demonstrated that calpains are overactivated originating serious cell death. Thus, the inhibition of this enzyme has been considered one of the strategies to treat neurodegenerative diseases [236-238]. Among the prepared hybrids, compound 60 (Fig. 32) was the most potent as µ-calpain inhibitor (IC50 = 0.13 µM) and also exhibited strong antioxidant activities in DPPH, superoxide anion radical scavenging and lipid peroxidation inhibition assays [235]. In addition, in order to obtain compounds with dual inhibition of lipid peroxidation and cellular calpain, Auvin et al. [239] prepared hybrid structures formed from the 2-hydroxy-tetrahydrofuran group, a masked aldehyde selected as a calpain pharmacophore, linked to a different antioxidants [239, 240]. In another study intending to obtain potent antioxidant compounds, Koufaki et al. [241] synthesized hybrids containing the chroman moiety of vitamin E and a catechol group and evaluated the influence on antioxidant activity of catechol groups at positions 2 or 5 of the chroman nucleus. The interesting compound 61 (Fig. 33) protected against

19

hydrogen peroxide-induced cellular damage (IC50 = 1 ± 0.1 µM), possibly due to its iron chelating properties, and compound 62 (Fig. 33) possessed a strong neuroprotective activity in glutamate-induced cell death of HT22 cells (EC50 = 0.93 ± 0.19 µM) that could be related not only to their antioxidant activity but also to their capacity to interfere with other cell signaling cascades implicated in oxytosis [241]. In later studies, it was combined the chroman nucleus of vitamin E and catechol derivatives, linked by heterocyclic five-membered rings such as 1,2,4-oxadiazole, 1,3,4oxadiazole, 1,2,3-triazole, tetrazole and isoxazole. Among the 2-substituted chroman analogues, compound 63 (Fig. 33), in which a 3,4-dimethoxyphenyl moiety is directly attached to the 1,2,4-oxadiazole ring, evidenced the highest antioxidant activity in the protection of glutamate-challenged HT22 cells (antiproliferative MTT assay: EC50 = 254 ± 65 nM) in the series of 2-substituted chroman analogues. In the same assay and concerning the 5-substituted chroman analogues, the isoxazole derivative 64 (Fig. 33) exhibited the strongest antioxidant activity, protecting from glutamateinduced oxidative cell destruction (antiproliferative MTT assay: EC50 = 245 ± 38 nM); however, this compound was cytotoxic, probably due to the presence of the chatecol moiety, while the triazole analogue 65 (Fig. 33) in spite of being less effective as antioxidant (EC50 = 801 ± 229 nM) was non-cytotoxic in all tested concentrations [242].

O HO

O N H

O

HO 60

N H

O

OH

Fig. (32). Chemical structures of the hybrid 60 having a strong antioxidant activity and µ-calpain inhibition, both important to the treatment of neurodegenerative diseases [235].

As previously mentioned, the oxidative deamination mediated by human MAOs produces highly reactive peroxides that may contribute to the oxidative damage observed in some neurodegenerative disorders [243, 244]. Considering this fact, a hybrid scaffold was developed combining the hydrazine moiety of iproniazid (Fig. 34), a known irreversible MAO inhibitor [245], and the thiazole nucleus of glitazone drugs (e.g. pioglitazone or rosiglitazone, Fig. 34), whose neuroprotective properties are also related to their ability to selectively inhibit the MAO-B [246]. Despite none of these compounds tested were able to inhibit the human MAO-A, the resulting hybrid structures demonstrated to be highly selective as human MAO-B inhibitors, with compounds 66a (IC50 = 350.03 ± 26.12 nM) and 66b (IC50 = 851.32 ± 64.78 nM) (Fig. 34) being the most potent ones [247]. 5. OTHER CNS DISEASES Depression is a CNS disorder usually related with a dysfunction of the central serotonergic neurotransmission and, therefore, the selective serotonin reuptake inhibitors

20


Matias et al.

OH O

OH

HO

NH

HO

O

OH

O

OH

O

N

O

O

O N

O 63

62

61 OH OH

OH

N O

N N N

OH

HO HO O O 64

65

Fig. (33). Chemical structures with antioxidant activity incorporating chroman moiety of vitamin E and a catechol group [241, 242]. O

N

N H

O

H N

O

HN O

Iproniazid

N S Pioglitazone COOEt

O

O

HN O

N N

N

N

R2 R1

S Rosiglitazone

N H

S S

66a: R1= CH3

R 2=

66b: R1= H

R 2=

N H

Fig. (34). Chemical structures of hybrids developed from hydrazine moiety of iproniazid and thiazole nucleus of glitazone drugs and these precursors [247].

appeared to be one of the most important class of antidepressant agents [248]. In this regard, Orús et al. [249] described the development of new hybrid structures with affinity for both the 5-HT1A receptor and the serotonin (5-HT) transporter. This study was based on coupling of structural moieties related to inhibition of serotonin reuptake, such as benzo[b]-thiophene derivatives to arylpiperazines, typical 5-HT1A receptor ligands. All of these compounds showed high affinity for both targets and structure-activity relationship analysis showed that the presence of a heteroatom in the aryl group bound to piperazine ring and its position appears to be critical for the affinity of 5-HT1A receptors, with the compounds derived from 8-quinolyl showing the best results [249]. More recently, a new drug named vilazodone, 5-{4-[4-(5-cyano-3-indolyl)-butyl]-1piperazinyl}2benzofuran-2-carboxamide, 67 (Fig. 35), was approved by the FDA for the treatment of major depressive disorder in adults [250, 251]. Interestingly, this drug is a hybrid with activity as selective serotonin reuptake inhibitor and as 5-HT1A receptor agonist, which resulted of the combination of a 5-cyano-indole-butyl-amine and

2-carboxamidebenzofurane-5-yl-piperazine moieties with a four-carbon-saturated linker between the indole and piperazine rings. This chain originated the optimal configuration for the high 5-HT1A receptor affinity and the introduction of the cyano group in 5-position on the indole ring increased serotonin transporter affinity [252, 253]. Cocaine addiction represents a public health problem and still does not exist pharmacotherapy approved that can lessen its abuse [254]. In a study intending to develop useful drugs for treating cocaine addiction, it was reported the preparation and pharmacologic evaluation of a series of (bisarylmethoxy)butylpiperidine hybrids having dual activity at the dopamine transporter and dopamine/serotonin receptor sites. Within all structures studied, compound 68 (Fig. 36) showed the highest affinity for dopamine transporter and it was observed that in this series, when a large halogen atom (Br) was introduced at the 4-position of the aromatic ring bound to piperidine, the selectivity and binding potency to this transporter were improved. This compound also showed a moderate dopamine D2/D3 receptor antagonism and



produced a significant increase in spontaneous locomotor activity in mice with an ED50 value of 2.42 mg/kg. Compound 69 (Fig. 36) evidenced to be the strongest binding ligand at the dopamine transporter (Ki = 1.32 ± 0.49 nM) and also showed moderate activity for the D2/D 3 receptor sites [255].

21

(Fig. 38) with a three carbon linker between the imidazole and the heterocyclic moiety, showing, in fact, high H 3 receptor affinity (Ki = 4.1 nM in [125I]Iodoproxyfan binding assay for human H3 receptors stably expressed in CHO cells) and high histamine N-methyltransferase inhibitory activity (IC50 = 0.024 ± 0.004 µM in histamine N-methyltransferase assay on isolated enzyme from rat kidney) [260].

O

NC

CONH2

O

N

O

O

N H

N

F 3C

67 70

Fig. (35). Chemical structure of vilazodone [252].

71 O

F

F

F

O

F N

N

N H

N

O 4

O

N

O

N

N H

N

F3C

HN

O

O

4 N Cl

OH

72

N

O NH

Br 68

Cl

Fig. (37). Chemical structures of the proposed hybrids as antiautism drug candidates [257].

69

Fig. (36). Chemical structures of the compounds synthesized to combat cocaine addiction [255].

Autism is a neurodevelopmental disorder that causes lifelong impairment and the serotonergic system may underlie the etiology of this disorder [256]. Using the tethering technique, a library of virtual ‘hybrid’ molecules incorporating 5-HT reuptake inhibitors and antagonists of the 5-HT1B/1D auto-receptors was created as anti-autism drug candidates. Then, proposed compounds with high fit values were selected for further synthesis and subsequent in vitro biological evaluation. Examples of these proposed compounds include the chemical entities 70, 71 and 72 (Fig. 37), and it was observed that the preliminary in vitro data are promising and consistent with the prediction studies [257]. Finally, the histamine H3 receptor has received particular attention over the past decade as a promising therapeutic target in a large variety of CNS diseases, such as neurodegenerative and psychiatric disorders. This has happened because this receptor can regulate the release of other important neurotransmitters such as acetylcholine, dopamine, norepinephrine and serotonin, which are involved in the pathogenesis of CNS diseases [258, 259]. In this context, a novel series of imidazole-containing compounds was synthesized and evaluated combining structural characteristics of both H3 receptor antagonists and histamine N-methyltransferase inhibitors [260]. In the development of these structures it was considered that potent H3 receptor antagonists containing the imidazole ring [261] and some heterocycles (e.g. tacrine) are also associated to Nmethyltransferase inhibition [262]. The most potent of these hybrid compounds was the aminoquinoline derivative 73

N N

N H N H

73

Fig. (38). Chemical structure of the hybrid with H3 receptor affinity and histamine N-methyltransferase inhibitory activity [260].

6. CONCLUSION The disorders that affect the CNS such as pain, epilepsy and neurodegenerative diseases have a complex and multifaceted pathogenesis involving several biochemical pathways. Over the years, due to their relevance, the molecular and cellular mechanisms underlying these CNS diseases are emerging, along with potential therapeutic targets. In this context, the development of new disease models is offering increasing opportunities to assess the potential of novel drug candidates. A relatively recent and increasingly relevant medicinal chemistry strategy for the design of therapeutic molecules with a multifunctional nature and potential application in these disorders is the hybridization approach. In fact, molecules consisting of two or more pharmacophores that are able to act through different action mechanisms are being developed aiming to find compounds with increased potencies and reduced side effects as well as improved pharmacokinetic profiles. In fact, an increasing number of studies are demonstrating that several hybrid molecules are revealing high efficacy and low toxicity in in vitro and in vivo models. In this review some of

22


these research works are discussed in order to highlight and compare new drug candidates that can improve the therapeutic outcomes in patients suffering from CNS-related diseases. At this point, it should be noted that the majority of the research studies poses a great emphasis on the most potent compounds; however, it is important to recognize that a greater potency does not necessarily mean a higher therapeutic efficacy. Hence, it is essential to be aware that after the synthesis of a new drug candidate, multiple simple in vitro tests and more complex in vivo assays in laboratory animals and also in man are required to provide evidence about the potential therapeutic interest of the compound. In order to achieve central analgesia, opioids based essentially on endogenous peptides that have natural analgesic power as well as opiates incorporating the fentanyl structure were developed. Additionally, new hybrid compounds have been studied to control neuropathic pain and epileptic seizures. In the last case, different and important nucleus included in drugs largely used in the clinic are linked to obtain interesting new anticonvulsant drug candidates. However, in the context of epilepsy, given the scarcity of knowledge regarding the mechanisms of action of the clinically available AEDs and also the gold-standard seizure models used to identify and evaluate anticonvulsant compounds (usually non-mechanistic models), the discovery of AEDs drugs is still not commonly based on specific targets in the 21st century, but rather in their potential to avoid seizures. For this reason, it is necessary to promote a better understanding of the complex mechanisms underlying epileptogenesis in order to progress in epilepsy drug research. The hybrid strategy has also been applied in the Table 1.

Matias et al.

search for new pharmacological alternatives to treat neurodegenerative diseases. In this scope, the development of anti-Alzheimer hybrid molecules are being extensively studied, mainly involving hybrids of tacrine, the first FDA approved cholinesterase inhibitor for the treatment of this disease. In this case, the anti-Alzheimer therapies, which are currently available in the market seem to have a specific target and this could be related to the ineffectiveness of the treatment of this multifactorial disease. Indeed, the multitarget drug design concept continues to be explored in other neurologic and psychiatric diseases, and vilazodone is a prominent example of a hybrid molecule approved by FDA for the treatment of major depressive disorder in adults. To summarize the information referred, accordingly with the CNS disorders discussed, a table was elaborated associating the pharmacophores explored with their putative mechanisms of action (Table 1). In this context, it is important to take into consideration that often the pharmacophores (frequently heterocycle rings) display many biological activities and, for this reason, a wide variety of mechanisms of action, known or unknown, could be involved and interconnected to allow that they possess different pharmacological and therapeutic properties. In conclusion, due to the emergent need of new therapeutic compounds for the treatment of complex CNS diseases, it is clear that the hybrid approach can afford molecules that can be safer and more effective and even more economical than classical drugs. Thus, in the near future, it is expected an increase in the number of potential multi-target drugs developed through this novel medicinal chemistry approach.

The pharmacophores and their main putative mechanisms of action accordingly with the central nervous system disorder in which they were evaluated. The pharmacophores are underlined.

Compound

Pharmacophores (main putative mechanism of action)

Ref.

1

Enkephalin (δ and µ opioid receptors agonism) + deltorphin (δ opioid receptor agonism)

[72]

2

Endomorphin-1 (µ opioid receptor agonism) + substance P (opioid system)

[79]

3

Endomorphine-2 (opioid receptor agonism) + DAMGO (µ opioid receptor agonism)

[80]

4

Fentanyl (µ opioid receptor agonism) + agmatine (imidazoline binding site interaction)

[81]

5a-5d

GABA (GABA agonism) + 1,2,4-triazole (P2X7 antagonism, σ opioid receptor inhibition)

[84]

6

GABA (GABA agonism) + benzothiazole (excitatory neurotransmission modulation)

[108]

7

Phthalimide (voltage-dependent sodium channel blockage) + GABA (GABA agonism) + anilide from ameltolide (voltagedependent sodium channel blockage)

[110, 111]

8

2,6-Dimethylphenyl amino from ameltolide (voltage-dependent sodium channel blockage) + GABA (GABA agonism)

[114]

9a-9b

1,5-Benzodiazepine (GABAA receptor agonism) + thiazolidine (tricarboxylic acid cycle oxidation inhibition)

[118, 263]

10a-10b

Aryl thiosemicarbazide (voltage-dependent sodium channel blockage) + 4-(aryloxy)phenyl semicarbazone (voltagedependent sodium channel blockage)

[123, 264]

11

Semicarbazone (voltage-dependent sodium channel blockage) + isatin (voltage-dependent sodium channel blockage)

[124]

Pain

Epilepsy



23

(Table 1) Contd….

Compound


Ref.

12a-12c

Semicarbazone (voltage-dependent sodium channel blockage) + isatin (voltage-dependent sodium channel blockage)

[126]

13

N-(3-methylpyridin-2-yl) semicarbazones (voltage-dependent sodium channel blockage) + pyridine (potassium channel blockage, excitatory neurotransmission modulation)

[127, 265]

14a-14b

Pyrrolidone (GABA mechanism) + pyridine (potassium channel blockage, excitatory neurotransmission modulation)

[129, 266]

15

Quinazolin-4-(3H)-one (GABAA receptor agonism) + 4-(aryloxy)phenyl semicarbazones (voltage-dependent sodium channel blockage)

[133]

16a-16b

Quinazolin-4-(3H)-one (GABAA receptor agonism) + benzothiazole (excitatory neurotransmission modulation)

[136]

17a-17b

Quinazolin-4-(3H)-one (GABAA receptor agonism) + benzothiazole (excitatory neurotransmission modulation)

[137]

18a-18b

Quinazolin-4-(3H)-one (GABAA receptor agonism) + tetrazole (GABA degradation inhibition)

[138, 267]

19

Quinazolin-4-(3H)-one (GABAA receptor agonism) + tetrazole (GABA degradation inhibition) + pyridine (potassium channel blockage, excitatory neurotransmission modulation)

[138]

20a-20b

Phenytoin (voltage-gated sodium channels blockage) + thiosemicarbazide (voltage-dependent sodium channel blockage)

[102]

21

Phenytoin (voltage-gated sodium channels blockage) + 1,3,4-oxadiazole (voltage-gated sodium channels blockage)

[102, 268]

22

Phenytoin (voltage-gated sodium channels blockage) + lidocaine (voltage-gated sodium channels blockage)

[140]

Alzheimer’s disease 23a-23d

Tacrine (AChE inhibition) + methylenedioxybenzene (self-induced Aβ aggregation inhibition)

[155]

24a-24c

Tacrine (AChE inhibition) + oxoisoaporphine (AChE inhibition)

[157]

25

Tacrine (AChE inhibition) + ferulic acid (antioxidant)

[159]

26a-26b

Tacrine (AChE inhibition) + ferulic acid (antioxidant) + nitric oxide (cerebral blood flow regulation)

[160]

27

6-Chlorotacrine (AChE inhibition) + caffeic acid (antioxidant)

[164]

28

6-Chlorotacrine (AChE inhibition) + mefenamic acid (antioxidant)

[168]

29

Tacrine (AChE inhibition) + flurbiprofen (γ-secretase inhibition) + nitric oxide (cerebral blood flow regulation)

[170]

30a

Tacrine (AChE inhibition) + o-amino benzylamine (metal chelation)

[171]

30b

Tacrine (AChE inhibition) + o-hydroxyl benzylamine (metal chelation)

[171]

31a-31b

Tacrine (AChE inhibition) + nimodipine (L-type voltage-dependent calcium channels blockage)

[172]

32, 33a-33-b

Tacrine (AChE inhibition) + phenylthiazole (tau protein aggregation inhibition)

[178]

34

6-Chlorotacrine (AChE inhibition) + carbazole from carvedilol (vasodilatation, antioxidant)

[179]

35

Tacrine (AChE inhibition) + carbazole (antioxidant)

[180]

36a-36b

Tacrine (AChE inhibition) + benzothiazole (Aβ-aggregation inhibition)

[182]

37a-37b

6-Chlorotacrine (AChE inhibition) + 5-phenylpyrano[3,2-c]quinolone (AChE peripheral site inhibition)

[183]

38

Tacrine (AChE inhibition) + 8-hydroxyquinoline (metal chelation, Aβ plaque load reduction)

[184]

39

Tacrine (AChE inhibition) + lophine (H3 receptor antagonism)

[185, 269]

40a

6-Chlorotacrine (AChE inhibition) + rhein (antioxidant)

[186]

40b-40c

Tacrine (AChE inhibition) + rhein (antioxidant)

41a-41d

Tacrine (AChE inhibition) + flavonoids (AChE inhibition, Aβ fibril formation inhibition, antioxidant, metal-chelation)

[189]

42

6-Chlorotacrine (AChE inhibition) + indanone from donepezil (AChE inhibition)

[190]

43

Tacrine (AChE inhibition) + indanone from donepezil (AChE inhibition)

[190]

24


Matias et al.

(Table 1) Contd….

Compound


Ref.

44a

6-Chlorotacrine (AChE inhibition) + donepezil (AChE inhibition)

[191]

44b

Tacrine (AChE inhibition) + donepezil (AChE inhibition)

[191]

45a-45b

Indanone from donepezil (AChE inhibition) + phenyl-N-methylbenzylamino from AP2238 (AChE inhibition)

[193]

46a

Benzylpiperidine from donepezil (AChE inhibition) + indolyl propargylamino from N-[(5-benzyloxy)-1-methyl-1H-indol2-yl)methyl]-N-methylprop-2-yn-1-amine (MAO inhibition)

[195]

46b

Benzylpiperidine from donepezil (AChE inhibition) + indole from compound 46a (AChE-induced Aβ aggregation inhibition)

[196]

47a-47b

Benzylpiperidine from donepezil (AChE inhibition) + 2-chloropyridine-3,5-dicarbonitrile (AChE inhibition)

[198]

48

Dimethoxyindanone from donepezil (AChE inhibition) + hupyridone from huperzine A (AChE inhibition)

[199]

49

Benzylpiperidine from donepezil (AChE inhibition) + N-protecting group (AChE interaction) + lipophilic α-hexyl ester (lipophilicity)

[202]

50a-50b

Berberine (antioxidant) + benzenediol (antioxidant)

[209]

51a-51b

Tacrine (AChE inhibition) + phenyl-benzothiazole (Aβ interaction)

[210, 270]

52

Berberine (antioxidant) + phenyl-benzothiazole (Aβ interaction)

[210]

53

Tacrine (AChE inhibition) + huprine Y (AChE inhibition)

[212]

54

Rhein (antioxidant) + huprine Y (AChE inhibition)

[214]

55, 56

Rosmarinic acid (antioxidant) + choline from acetylcholine (AChE interaction)

[215]

Parkinson’s disease 57

Pramipexole (D3 receptor agonism) + arylpiperazine (D3 receptor agonism)

[231]

58

7-Hydroxy-2-(dipropylamino)tetralin (D3 receptor agonism) + arylpiperazine (D3 receptor agonism)

[231]

59a-59b

Aminotetraline (D3 receptor agonism) + piperazine (D3 receptor agonism)

[232]

General neurodegenerative diseases 60

Caffeic acid (antioxidant) + MDL 28170 (calpain inhibition)

[235]

61, 62

Chroman from vitamin E (antioxidant) + catechol (antioxidant)

[241]

63

Chroman from vitamin E (antioxidant) + catechol (antioxidant) + 1,2,4-oxadiazole (Aβ interaction)

[242]

64

Chroman from vitamin E (antioxidant) + catechol (antioxidant) + isoxazole (Aβ interaction)

[242]

65

Chroman from vitamin E (antioxidant) + catechol (antioxidant) + triazole (Aβ interaction)

[242]

66a-66b

Hydrazine from iproniazid (MAO inhibition) + thiazole from glitazone (MAO-B inhibition)

[247]

5-Cyano-indole-butyl-amine (serotonin reuptake inhibition) + 2-carboxamidebenzofurane-5-yl-piperazine (5-HT1A receptor agonism)

[252, 253]

Depression 67

Cocaine addiction 68

(Bisarylmethoxy)ethyl (dopamine transportation) + 4-aryl-4-piperidinol from bromperidol (dopamine D2/D3 antagonism)

[255]

69

(Bisarylmethoxy)ethyl (dopamine transportation) + pimozide (dopamine antagonism)

[255]

Benzyloxy halogenated benzene from fluoxetine (serotonin reuptake inhibition) + N-(4-methoxy-phenyl)amide (5-HT1B/1D autoreceptors antagonism)

[257]

Autism 70, 71



25

(Table 1) Contd….

Compound


Ref.

72

Phenylquinoxaline from sertraline (serotonin reuptake inhibition) + N-(4-methoxy-phenyl)amide and 4-methylpiperazine from GR-127935 (5-HT1B/1D autoreceptors antagonism)

[257]

Neurodegenerative and psychiatric disorders 73

Imidazole (H3 receptor antagonism) + aminoquinoline from amodiaquine (histamine N-methyltransferase inhibition)

LIST OF ABBREVIATIONS 5-HT

= Serotonin

7-OH-DPAT = 7-Hydroxy-2-(dipropylamino)tetralin

POPH–QREN, which is co-funded by FSE and MEC. The authors also acknowledge the support provided by COMPETE program through the strategic project Pest-OE/ SAU/UI0709/2014.

AChE

= Acetylcholinesterase

AD

= Alzheimer’s disease

AED

= Antiepileptic drug

Aβ

= Amyloid β-protein

BBB

= Blood-brain barrier

BuChE

= Butyrylcholinesterase

CAS

= Catalytic anionic site

CNS

= Central nervous system

DPPH

= 1,1-Diphenyl-2-picrylhydrazyl

ED50

=

FDA

= Food and Drug Administration

GABA

= γ-aminobutyric acid

IC50

= Median inhibitory concentration

MAO

= Monoamine oxidase

MES

= Electroshock seizures model

[9]

NMDA

= N-methyl D-aspartate

[10]

PAMPA

= Parallel artificial membrane permeability assay

PAS

= Peripheral anionic site

PD

= Parkinson’s diseases

ROS

= Reactive oxygen species

scPTZ

= Subcutaneous pentylenetetrazole

TD50

=

Median effective dose

Median toxic dose

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CONFLICT OF INTEREST

[14]

The author(s) confirm that this article content has no conflict of interest.

[15]

ACKNOWLEDGEMENTS

[16]

The authors are grateful to Fundação para a Ciência e a Tecnologia (Lisbon, Portugal) for the PhD fellowship of Mariana Matias (SFHR/BD/85279/2012), involving the

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PMID: 27834131