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Current Medicinal Chemistry, 2011, 18, 144-161

Natural and Synthetic Naphthoquinones Active Against Trypanosoma Cruzi: An Initial Step Towards New Drugs for Chagas Disease Cristian O. Salas1, Mario Faúndez1, Antonio Morello2, Juan Diego Maya2 and Ricardo A. Tapia*,1 1

Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Santiago 6094411, Chile

2

Facultad de Medicina, ICBM, Universidad de Chile, Casilla 70086, Santiago-7, Chile Abstract: Chagas disease is one of the most important endemic diseases in Latin America, caused by Trypanosoma cruzi. The drugs used for the treatment of this disease, nifurtimox and benznidazole, are toxic and present severe side effects. The need of effective drugs, without adverse effects, has stimulated the search for new compounds with potential clinical utility. An overview of a number of natural naphthoquinones tested against T. cruzi parasites is provided. Among natural naphthoquinones, lapachol, -lapachone and its -isomer have demonstrated useful trypanocidal activities. In the search for new trypanocidal agents, this review outlines different structural modifications of natural quinones, as well as synthetic quinones, which have been subjected to trypanocidal studies. This review summarizes the mechanism of action and structure-activity relationships of the quinone derivatives, including some theoretical calculations that discuss the correlation of stereo electronic properties with the trypanocidal activity. In this context, this review will be useful for the development of new antichagasic drugs based mainly on structural modification of natural quinones.

Keywords: Chagas disease, lapachol, lapachones, naphthoquinones, structure-activity relationships, Trypanosoma cruzi, trypanocidal effects. 1. INTRODUCTION

1.1. Biological Cycle of Trypanosoma Cruzi

Chagas disease or American Trypanosomiasis is a pathological condition derived from infection by Trypanosoma cruzi on mammalian organisms. This is a zoonotic infection transmitted by blood-sucking triatomid insect commonly named vinchuca (or kissing bug). There are around to 8–11 million people infected, resulting in over 15,000 deaths per year [1]. This disease occurs mainly in rural areas; however, recently it has also been found in urban areas [2-4] and as a result of human migration, in developed countries [5-7]. This disease has been present in the American continent for more than 9,000 years and now extends from southern California to the southern tip of Argentina [8].

Trypanosoma cruzi has a complex life cycle, involving both mammalian hosts and insect vectors. The infection is transmitted by blood-sucking triatomid bugs, when the bite wound is contaminated with insect feces containing the nonreplicative trypomastigote form of the parasite. Once inside the host, trypomastigotes enters any nucleated cell and transform into the replicative amastigote form [13,14]. After several replicative cycles, cells become loaded with amastigotes that transforms into trypomastigotes. These are freed to infect nearby cells and to enter the circulation, which disseminates the infection in the host. The parasite life cycle is closed when a triatomid insect sucks host's infected blood. The ingested trypomastigotes transform into the replicative epimastigote form in the insect’s midgut [15].

Chagas disease is characterized by three clinical phases, named acute, indeterminate and chronic, that differ in symptoms and morbidity. The acute phase begins between one or two weeks after infection, however, the diagnosis is established in less than 10% of cases, possibly due to mild symptoms. The clinical course in most cases is towards spontaneous recovery [9], followed by an asymptomatic period, the indeterminate phase, that can last 10-20 years where parasitemia is minimal, but serology is positive [10]. Finally in the chronic phase, about 30% of those patients infected develop cardiac or digestive symptoms, characterized by myocarditis, and megacolon and megaesophagus. Mortality in the chronic phase is mainly due to the cardiomyopathy. Importantly, all available treatments have proven most effective in the acute phase of disease and in children [11,12].

*Address correspondence to this author at the Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Santiago 6094411, Chile; Tel: +56-2-6864429; Fax: +56-2-6864744; E-mail: [email protected] 0929-8673/11 $58.00+.00

Vector transmission is the most frequent way to acquire the infection; however, there are other modalities such as blood transfusion, congenital transmission, and transplant from infected donors or ingesting contaminated drinks [16,17]. 1.2. Models for Drug Development to Chagas Disease Despite the number of fatalities and the high costs associated with this pathology, pharmaceutical companies have not shown a real interest in the development of new drugs for Chagas disease. Moreover, nifurtimox and benznidazole have been the basic treatment from almost 30 years. In this context it is of utmost importance to develop new antichagasic molecules that are effective and have little or null side effects [18]. In this sense, scientists have developed in vitro and in vivo models for the study of this condition, ranging from molecular biology of the parasite to its relationship with © 2011 Bentham Science Publishers Ltd.

Natural and Synthetic Trypanocidal Naphthoquinones

Current Medicinal Chemistry, 2011 Vol. 18, No. 1

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O N O2N

N

N

O

N N H

SO2 H3C Nifurtimox

NO2 Benznidazole

Scheme 1. Chemical structure of clinical used drugs for Chagas disease.

various ecosystems including their associated vectors. The most used parasite forms are epimastigotes because, although not infective, they are easily cultured. However, this model cannot assess the differential impact of various compounds in the host-parasite relationship because epimastigotes are unable to infect. This is the reason why trypomastigotes are more suitable for such studies. Even more, in vitro studies are more reliable when the intracellular model is used, because this is a more approximate approach to the in vivo disease [11]. With this model the effect of potential trypanocidal agents upon intracellular parasite proliferation (endocytic index) and the release of trypomastigotes to the culture medium, can be assessed [19]. Conversely, in vivo models of acute and chronic Chagas disease allow assess different pharmacological parameters such as effectiveness, toxicity to the host, dose, pharmacokinetic properties, etc [19-22]. 1.3. Current Chemotherapy to Chagas Disease Two drugs are currently approved for treatment of Chagas disease, nifurtimox (4[(5-nitrofurfurylidene)amino]-3methylthiomorpholine-1,1-dioxide), derived from nitrofuran, and benznidazole (N-benzyl-2-nitroimidazole-1-acetamide), a nitroimidazole derivative (Scheme 1) [4,14]. The use of these drugs to treat the acute phase of the disease is widely accepted. However, their use in the treatment of the chronic phase is controversial. The undesirable side effects of both drugs, especially in adults, are a major drawback in their use, frequently forcing the physician to stop treatment [14]. The most frequent adverse effects observed in the use of nifurtimox are: anorexia, loss of weight, psychic alterations, excitability, sleepiness, digestive manifestations, such as nausea or vomiting, and occasionally intestinal colic and diarrhea. In the case of benznidazole, skin manifestations are the most notable (e.g., hypersensitivity and dermatitis with cutaneous eruptions). The more severe manifestations are depression of bone marrow, thrombocytopenic purpura and agranulocytosis [23,24]. Experimental toxicity studies with nifurtimox evidenced neurotoxicity, testicular damage, ovarian toxicity, and deleterious effects in adrenal, colon, oesophageal and mammary tissue. In the case of benznidazole, deleterious effects were observed in adrenal, colon and oesophagus. Benznidazole also inhibits the metabolism of several xenobiotics biotransformed by the cytochrome P450 system and its reactive metabolites react with fetal components in vivo. Both drugs exhibit significant mutagenic effects and were shown to be tumorigenic or carcinogenic in some studies. The toxic side effects or therapeutic effect of both nitroheterocyclic derivatives involve in vivo reduction of their nitro group (nitroreductases). In mammalian those processes are fundamentally mediated by NADPH-cytochrome P450 reductase or xanthine oxidoreductase; aldehyde oxidase may

also be involved. In parasites it is mediated by type I nitroreductases [4,23]. 1.4. Mechanism of Action of Nifurtimox and Benznidazole Both nitroheterocyclic compounds are characterized by a nitro group linked to an aromatic ring [12]. These agents function as prodrugs and must undergo enzyme-mediated activation within the pathogen or the host in order to have cytotoxic effects. These reactions are catalyzed by nitroreductases (NTRs) (Scheme 2). Based on oxygen sensitivity, NTRs are divided into two groups [25]. Type I NTRs are oxygen-insensitive, contain FMN as a cofactor and function via a series of two-electron reductions of the conserved nitro group, leading to moieties that promote DNA damage. This class of NTR is characteristically bacterial. The only trypanosomal enzyme shown to mediate this type of activity is prostaglandin F2 synthase (also known as ‘‘old yellow enzyme’’) [26], although only under anaerobic conditions. Type II NTRs are ubiquitous oxygensensitive FAD- or FMN-containing enzymes that mediate a one electron reduction of the nitro group generating an unstable nitroradical. In the presence of oxygen, this radical undergoes futile cycling to produce superoxide, with the subsequent regeneration of the parent nitro-compound [25]. In trypanosomes, type II activity has been proposed as the main activation mechanism [14,27-32]. Recently, [4,25] it has been demonstrated that type I NTR has the capacity to metabolize a wide range of nitroheterocyclic drugs, and that a reduction in this activity in both T. cruzi and T. brucei confers resistance to nitroheterocyclic trypanocidal agents. Thus, it is possibly that the oxidative stress induced by the type II NTRs activity could be only a minor role in the trypanocidal activity of these nitroheterocyclic agents. 1.5. Antioxidants Defenses as Target for Drug Development The knowledge of biochemical and genome sequence analysis of Trypanosoma cruzi, has led to identify a large number of trypanosomatid enzymes and/or biochemical pathways as potential targets for drug development [33]. Thus, several targets are being identified for currently approved drugs or new chemical structure screening with trypanocidal potential and these studies has led to structureactivity relationships for some of these molecules. Sterol biosynthesis, purine metabolism, thiol metabolism, cysteine proteases, polyamine biosynthesis and respiratory chain have been intensively investigated and important differences were identified between these targets of the parasite and its mammalian hosts, which could be exploited as chemotherapeutic targets [34-37]. For previous reviews about developments on the Chagas disease chemotherapy, see references [38-43].

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Scheme 2. Activation of antichagasic nitroheterocyclic drugs. The nitroheterocyclic drugs are substrates of nitroreductases. Under aerobic conditions, the nitro radical generated by the Type II nitroreductase undergoes futile cycling to produce superoxide, with the subsequent regeneration of the parent nitro-compound. Then, superoxide can be converted to hydroxyl radical through a Fenton reaction, generating radical oxygen species (ROS), inducing oxidative stress through macromolecular damage. On the other side, Type I nitroreductase, oxygen insensitive, donates four electrons generating hydroxylamine, which is electrophilic and capable of interact with macromolecules. In general, the mammalian host has a more wide and strong antioxidant mechanisms as compared with trypanosoma, thus rendering them more sensitive to this type of toxicity.

Several studies have postulated that the antioxidant capacity of the parasite is poor as compared with the mammalian host. Fundamentally, this observation is based on a relative deficiency in the total content of reduced low molecular weight thiols such as glutathione [13,44]. Nevertheless, the antioxidant system in T. cruzi is complex. Due to the absence of antioxidant enzymes, such as glutathione reductase, it was believed that the parasite defense mechanism were insufficient, and relied on the exclusive low molecular weight thiol bis glutathionyl spermidine, trypanothione. However, this molecule is only part of a more complex system that includes antioxidant proteins such as tryparedoxins and enzymes such as tryparedoxin peroxidase, glutathione peroxidase-like tryparedoxin peroxidases I and II and, ascorbate-dependent peroxidase, as well as superoxide dismutase [45]. Thus, the pleiotropic functions of the trypanothione-tryparedoxin system constitute an ideal target for chemotherapy, especially at the initial steps [46,47]. In this regard, inhibition of thiol content in the parasite with buthionine sulfoximine (BSO), an inhibitor of gamma-glutamyl-cisteinyl-glycine, pacemaker enzyme in the synthesis of glutathione and trypanotione, has demonstrated to be an attractive strategy, because it increased the effect of the antichagasics nifurtimox and benznidazole. In addition, BSO demonstrated an in vivo trypanocidal action itself [13,22].

2. NATURAL NAPHTHOQUINONES TRYPANOCIAL ACTIVITIES

WITH

Many natural compounds have been screened against Trypanosoma cruzi and studied as potential antichagasic drugs [14,48-53]; one of this group correspond to naphthoquinones. Among natural naphthoquinones, lapachol (1), lapachone (2), and its -isomer (3) have demonstrated trypanocidal activity (Fig. 1). These bioactive quinones were isolated from the heartwood of trees of the Bignoniaceae family (Tabebuia sp). They can also be found in other families such as Verbenaceae, Proteaceae, Leguminosae, Sapotaceae, Scrophulariaceae, and Malvaceae. The inner bark of Tabebuia avellanedae, commonly known as "pau d'arco" (lapacho, taheebo), is used as analgesic, anti-inflammatory, antineoplastic and a diuretic by the local people in the northeastern regions of Brazil [54,55]. -Lapachone (2), was found to be cytotoxic to a variety of human cancers [56-58], and some of this mechanism of action is also responsible of its trypanocidal behavior, such as inhibitor of DNA topoisomerase II [59,60], inducing a novel caspase- and p53-independent cell death pathway in human cancer cell lineages overexpressing NQO1 [58,61,62], increasing of oxygen radical production and cytotoxicity, etc. [57,63-67]. The trypanocidal action of these



147

O O

O

O

OH CH3 O

O O

O

CH3

CH3 CH3 1 Lapachol

2

3

-Lapachone

-Lapachone

Fig. (1). Natural napthoquinones with trypanocidal activities.

quinones is probably mediated by the production ROS and electrophilic metabolites, which bind to and inactivate T. cruzi macromolecules (Scheme 3) [68]. Juglone (4) and plumbagin (5) (Fig. 2), have been found to be active on epimastigote forms, leading to the total lysis of bloodstream trypomastigotes at a concentration similar to that of crystal violet, the standard drug recommended for the chemoprophylaxis of banked blood [69-71]. The related diospyrin (6) (Fig. 2), a dimer of 7-methyljuglone isolated from the Indian plant Diospyros montana [72-74], and four synthetic derivatives were assayed on intracellular forms of T. cruzi. The dimethyl ether derivative was found to be more active than the parent compound [75]. OH

O

O OH

R

O

H3C OH

O

O H3C O

4 R=H 5 R = CH3

6

Fig. (2). Other natural quinones active against T. cruzi, juglone, plumbagin and diospyrin.

A group of naphthofuranequinones (7-12), which were isolated from isolated from Tabebuia cassinoides, Tabebuia avellanedae, Crescentia cujete and other natural source, show several biological properties such as, in vitro cytotoxicity against KB, K562, and P388 cells, and antileukemic activity [76-79]. These quinones have been tested against T. cruzi and most of them showed an inhibitory effect on culture growth and on the parasite respiration [78,80] (Fig. 3). Houghton et al., reported the biological properties of extracts of the rootbark and stem bark of Kigelia pinnata DC (Bignoniaceae) and the subsequent isolation of active compounds, such as naphthofuranequinone 10, which showed activity against protozoan parasites. Compound 10 shows pronounced activity against Trypanosoma brucei brucei and Trypanosoma brucei rhodiense in vitro, with IC50 values of 0.12 and 0.045 μM, respectively [76,77]. The naphthofuranequinone 13, which has been isolated from Calceolaria sessilis, is the most active metabolite of this natural source against epimastigotes T. cruzi culture and exhibits lower IC50 values than the control drugs. Compound 13 also inhibited

the growth of methotrexate-resistant tumoral cells, with values of 2.1 - 5.0 μM [80]. The mechanism, in both cases, is through the generation of reactive oxygen species [80]. 3. SYNTHETIC NAPHTHOQUINONES TRYPANOCIDAL ACTIVITIES

WITH

The need for chemotherapeutic agents that are effective against all strains of T. cruzi, and with fewer or no side effects than those currently available, has prompted the synthesis of a number of natural naphthoquinone derivatives. These have been assayed as trypanocidal agents, some of these products showing promising biological properties. 3.1. Trypanocidal Activity of -Lapachone and Naphthoquinone Derivatives Among o-naphthoquinones, -lapachone 2 has been taken as starting material for screening trypanocidal drugs, due to the fact that -lapachone 2 is easily obtained from natural sources of quinones, or synthesized in good yields from simple substrates [81-84]. These aspects and the promising biologic properties, such as, a potent cytostatic agent in different human tumor cells [85-87] and the antiprotozoal activities of this naphthoquinone [88,89], have been identified as possible leads for drug development. Stoppani et al. [90,91] have studied a series of onaphthoquinones named CG8-935 (3,4-dihydro-2-methyl-2ethyl-2H-naphtho[1,2b]- pyran-5,6-dione) 14, CG9-442 (3,4dihydro-2-methyl-2-phenyl-2H-naphtho[1,2b]pyran-5,6-dione, 2-phenyl--lapachone) 16 and CG10-248 (3,4-dihydro-2,2dimethyl-9-chloro-2H-naphtho[1,2b]pyran-5,6-dione) 15 (Fig. 4). Among these compounds, 15 proved to be the most active in inducing oxidative damage on trypanosomatids [92,93]. The mechanism of action of these compounds involves the increase of oxygen radical production. The cytotoxicity was supported by the spectroscopic observation of lapachone (2), CG 8-935, CG 9-442 and CG 10-248 and the redox cycling, as well as by the production of the semiquinone radical, superoxide anion radical and H2O2 and the effect of this naphthoquinones on cell respiration as pivotal in the biological effects of naphthoquinones. Mansonones structural analogs 17 and 18 (Fig. 4), in the same study, showed a similar behavior to that of -lapachone derivatives [92-94]. Pinto et al., have synthesized -lapachone derivatives through the reaction of these naphthoquinones with common reagents, leading to several heterocyclic compounds [81,82,95,96]. These were grouped as oxazolic, imidazolic,


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Phosphate-pentose pathway

Cytochrome P450 Reductase

NADP

NADPH

FADOX

FADRED

+ e-

O

O O

O

R

R O

O Semiquinone Radical

Quinone

Oxidative damage to DNA

- e-

Protein and lipids peroxidation

O2

O2

OH + O2

Covalent bond to nucleic acids Fe+3 Superoxide Dismutase

Enzimatic inactively

Covalent bond to proteins (enzimatic inactively)

O2

Catalase H2O + O2

H2O2 NADPH 2GSH Glutathione Peroxidase

Glutathione Reductase GS-SG

NADP+

2H2O

Scheme 3. Schematic representation of p-quinone metabolism, redox cycling and production of electrophilic metabolites [68]. Quinones are reduced by cytochrome P450 reductase yielding a semiquinone radical that bonds covalently to proteins and nucleic acids. However, in aerobic conditions, this semiquinone radical reacts with oxygen undergoing a futile cycle, regenerating the quinone and simultaneously, producing superoxide, which is converted to hydrogen peroxide by the action of superoxide dismutase. This hydrogen peroxide has several fates: Through catalase is converted in H2O; in a Haber-Weiss reaction is converted in OH •–, reactive oxygen radical implicated in oxidative damage to macromolecules; finally, through a glutathione peroxidase reaction, converted in H2O using glutathione as an electron donor. In general, the mammalian host has a more wide and strong antioxidant mechanisms as compared with trypanosoma, thus rendering them more sensitive to this type of toxicity.



O

O

R1

O

149

CH2OH O R

O

O

O

R

7 R=H 8 R = OH

O

OH R2

O

9R=H 10 R = OH O

O

11 R1 = CH3; R2 = H 12 R1 = H; R2 = CH3 CH3 CH3

O

CH3

O 13

Fig. (3). Structures of natural naphthofuranequinones with trypanocidal activities. O O O

O

O

O

O Cl O

O

14

15

16

O

O O

O

O

O 18

17 Trypanocidal

Compounds

Activity

14

15

16

17

18

IC50 (μM)*

0.3

0.4

0.7

0.4

0.1

* IC50 is the drug concentration in μM needed to lower the growth by 50% in culture of C. fasciculate.

Fig. (4). Trypanocidal activity of -lapachone derivatives and structural analogs.

phenoxazonic, indolic, pyranic and cyclopentenic derivatives. Among the cyclofunctionalised products the oxazolic and imidazolic derivatives showed 1.5 to 34.8 times higher activity, respectively than crystal violet, the standard product for sterilization of stored blood. The evaluation of these compounds, together with that of the original natural naphthoquinones, was performed using bloodstream trypomastigote forms of T. cruzi, and by comparing the activities of the original naphthoquinones with the synthetic compounds. The authors concluded that structural features involving an increase in lipophilicity led to an enhanced trypanocidal ac-

tivity. It is possible that an increase in lipophilic character allows for better penetration of the compound through the plasma membrane of the parasite. Among all the screened compounds, three naphthoimidazoles derivatives from lapachone 2, with the aromatic moieties linked to the imidazole ring, 19, 20 and 21 (Fig. 5), showed the highest activity on trypomastigote forms and were further investigated. These molecules were also active on intracellular amastigotes and epimastigotes, and presented low toxicity to host cells. In epimastigotes, their exactly mode of action upon the parasite appears to be complex; however, damage caused by


Salas et al.

NH

N

N NH

NH

O

NH

O

19

F

N

O

20

21 Compounds

Trypanocidal Activity

19

20

21

ED50 /24 h (μM)*

15.4

37.0

243.3

* ED50 values, corresponding to the concentration in μM that causes lysis of 50% of the parasites at 24h of incubation.

Fig. (5). Trypanocidal effect of imidazolic derivatives of -lapachone on bloodstream trypomastigotes of T. cruzi. O

O

O O

O

O

-lapachone (2)

O

22

ICkc50 (μM)a % viability a b

b

O

O

OH 23

24

Compounds


O

O

O

-lapachone

22

23

24

0,21

1,93

3,75

4,01

4,8

40,3

30,4

-

ICkc50 is the drug concentration in μM needed to lower the growth constant (kc) by 50% in culture of epimastigotes form. % viability of T. cruzi trypomastigote respect to control (100%), carried out using drug concentrations equivalent to ICkc50 .

Fig. (6). Effect of -lapachone and its derivatives upon culture growth in T. cruzi epimastigote and trypomastigote forms.

oxidative stress is excluded, since, unlike the original onaphthoquinones 19, 20 and 21, they do not easily undergo redox reactions [97-100]. It is important to note that several trypanocidal agents, such as benznidazole, contain imidazole moieties [101], which is consistent with the idea that the trypanocidal activity is associated with the imidazole skeleton. Tapia et al., have synthesized other -lapachone analogs, such as 22 and 23, and nor--lapachone analog 24 (Fig. 6). These compounds were screened against T. cruzi epimastigotes Tulahuén strains, as described earlier [68,102]. These compounds inhibit parasite growth and exhibit ICkc50 values lower than those of the drugs used in this study: nifurtimox has a value of 9.62 μM and benznidazole, 20.6 μM, respectively. -Lapachone derivatives 22 and 23 were less active than -lapachone 2, indicating that a hydroxyl group at C-3

and one methyl group at C-2 diminish the activity compared with the natural product. It is well known that the ability of these compounds to produce free radicals in the parasite is a mechanism for the trypanocidal activity of quinones and in experiments of oxygen uptake in cellular respiration it was measured at the ICkc50 concentrations. Quinone addition may produce an increase (redox cycling), a decrease or no alteration in oxygen uptake. -Lapachone 2 and quinones 22 and 23 do not inhibit cellular respiration neither produce redox cycling. The trypanocidal action of these compounds is probably mediated by the production of electrophilic metabolites, which bind to inactivate T. cruzi macromolecules (Scheme 3). Fig. 6 shows the activity of -lapachone derivatives upon trypomastigote viability at ICkc50 drug concentrations. These forms are found in mammalian blood and are the target for anti-chagasic drugs. A viability test, such as MTT reduction, was carried out using drug concentrations



151

O O

O

O O

O

O

O

R

NH O

R O

R1

N

O

O

N

R2

X 25a X= H bX=I

N

26a R = NH-Ph b R = OH c R = N3

27a R1 = NO2 ; R2 = H b R1 = H ; R2 = OCH3

Trypanocidal

28a R = Ph b R = Cy,OH

Compounds

Activity

25a

25b

26a

26b

26c

27a

27b

28a

28b

IC50/24h (μM)*

398

641

199

212

50.2

86.3

88.2

17.3

57.8

* IC50 values corresponding to the concentration in μM that causes lysis of 50% in culture of trypomastigote form at 24h of incubation.

Fig. (7). Trypanocidal effect of nor--lapachone derivatives on bloodstream trypomastigote form of T. cruzi.

equivalent to ICkc50 values for epimastigotes. Derivatives 22 and 23 showed stronger activity against T. cruzi than nifurtimox or benznidazole. These results indicate that mitochondrial reductase damage is very important in cytotoxicity experiments [68]. On the other hand, nor--lapachone analog 24, is less active than -lapachone 2 and its derivatives 22 and 23 and, as nifurtimox, produces a high increase of oxygen uptake, indicating a significant redox cycling, in contrast to the mechanism of -lapachone 2 and its derivatives 22 and 23 [102]. Other nor--lapachone derivatives have been synthesized and screened in T. cruzi culture. De Castro et al. [103], described for the first time in the literature the synthesis of 25b and 26b and, although the synthesis of 25a had been described long time ago, there is no report about its biological activity. In vitro assays with bloodstream forms of T. cruzi resulted in to IC50/24 h values for 25a, 25b and 26a in the range of 157–640 μM, while the corresponding value for crystal violet, the standard compound, was 536 ± 3 μM (Fig. 7). Quinone 25b showed the highest activity among the assayed naphthoquinones; comparison between 25a and 26a revealed that the presence of an iodine atom led to a 1.6-fold increase in the trypanocidal activity [99]. A similar activity increase against T. cruzi has been reported in studies with culture epimastigote forms treated with bromine furanquinones [102]. This study also showed that quinones 25a, 25b and 26a inhibit epimastigote proliferation [103]. The aminated compound 26a presents a high trypanocidal activity and the lack of previous reports in the literature on amino naphthofuranquinones has stimulated the synthesis of compounds with aminated groups linked to the furane ring. In another study of these series it was reported that lapachol 1 and -lapachone 2 display similar activities against T. cruzi, which were higher than that of crystal violet, whereas nor-lapachone 24, -lapachone 3, and lawsone were inactive [81]. Furthermore, de Castro et al. prepared several derivatives of nor-lapachone 24; some of them are shown in Fig. (7). These compounds were assayed for the first time against T.

cruzi [104]. Naphthoquinone 26b, which presents important activity against methicillin-resistant bacterial strains [104], showed an activity only two-fold lower than that of benznidazole. In the same experimental conditions, the corresponding IC50 value for benznidazole is 103.6 ± 0.6 μM [105], and for crystal violet, 536.0 ± 3.0 μM [81]. On the other hand, the authors synthesized a group of arylamines substituted by electron-withdrawing and electron-donating groups and were also evaluated against T. cruzi [104]. Compounds 27a and 27b were both more active than benznidazole, these results suggest that the functional groups affects the electronic distribution of the system as well as the redox potential of the quinone center. Approaches on the planning of new trypanocidal compounds based on molecular hybridization were made by de Castro et al. [105], by preparing the new [1,2,3]triazolyl naphthoquinones 28a and 28b, from 26c. These compounds proved to be more active against the T. cruzi than their original precursor nor--lapachone 24, and such activity was especially dependent on structural features and on the substituent position on the furane ring. Compounds 26c, 28a and 28b were assayed against the infective bloodstream trypomastigote form of T. cruzi and these derivatives were more active than the original quinone, with IC50/24h values in the range 17-57 μM (benznidazole had IC50/ 24h of 103.6 ± 0.6 μM). These results show that the triazole nucleus increases the biological activity, the apolar substituted triazole 28a being the most active. These triazole derivatives of nor--lapachone emerge as interesting new lead compounds in the drugs development for the treatment of Chagas disease. 3.2. Trypanocidal Activity of -Lapachone and Naphthoquinone Derivatives Last year several, -lapachone derivatives were synthesized and their biological properties evaluated [66,106-108]. Although -isomers were found more active, there are examples indicating that some structural modifications produce -lapachone derivatives with interesting anti-trypanosoma properties [68]. Fig. (8) shows a group of naphthoquinones


Salas et al.

O O

O O

O

O O

O O

O -Lapachone

O

O

29

30

O

O

O

31

O O OCH3 O

O O

N

O O

N

O

O O

32

O

33

OH

O

34

Trypanocidal

35

Compounds

Activity

-lapachone

29

30

31

32

33

34

35

ICkc50 (μM)*

24.7

24.5

36.3

22.2

26.2

38.1

0.19

20.1

* ICkc50 is the drug concentration in μM needed to lower the growth constant (kc) by 50% in culture of epimastigotes form.

Fig. (8). Effect of -lapachone and its derivatives upon culture growth in T. cruzi epimastigote form.

that were tested on the growth of Tulahuén strain of T. cruzi: and all of these compounds inhibit parasite growth. Some of them present ICkc50 values higher than 20 μM and are equipotent when compared with nifurtimox and benznidazole, and thus devoid of pharmacological interest. The most active compound among -lapachone derivatives was pyranoquinolinequinone 34, with an ICkc50 lower than that of current antichagasic drugs (50 times and 108 times lower than nifurtimox and benznidazole, respectively). This result is very interesting because normally -lapachones have a weak trypanocidal activity [109-112], indicating that nitrogen substitution in the aromatic ring increases the trypanocidal activity of these compounds. Trying to understand the mechanism of trypanocidal effects, the ability of these compounds to produce free radicals in the parasite was evaluated. This is a well-known mechanism for the trypanocidal activity of quinones [111,113-115]. To evaluate this possibility, experiments of oxygen uptake were conducted, where cellular respiration was measured at the ICkc50 concentrations. Quinone addition may produce an increase (redox cycling), a decrease or no alteration in oxygen uptake. Nifurtimox and quinones 29, 30, 31, and 35 increase oxygen uptake and present high oxygen redox cycling (Scheme 3), indicating that reactive oxygen species, such as superoxide anion and hydroxyl radicals, are generated, inducing oxidative stress. On the other hand, -lapachone 3, and quinone 33 do not inhibit cellular respiration neither produce redox cycling. The trypanocidal action of these compounds is probably mediated by the pro-

duction of electrophilic metabolites, which bind to inactivate T. cruzi macromolecules (Scheme 3). Finally, this study shows that lapachol 1 and compounds 31 and 34 diminish oxygen uptake and probably inhibit cellular respiration. Other groups of molecules, such as -lapachone 3 and nor--lapachone derivatives, were synthesized by Tapia et al. [102], and tested their in vitro trypanocidal activity. Fig. (9) shows compounds with inhibition activity higher than 80% at 5 μM concentration; also these quinones present ICkc50 values between 1 and 4 μM and had more potent trypanocidal activity than nifurtimox and benznidazole. The introduction of a bromine atom in the benzoquinone ring contributes substantially to the trypanocidal activity of bromobenzofurandiones 36 and 37, indicating that the presence of the halogen atom in the molecule is important. In this study, a comparison of tricyclic quinones indicates that the most active compounds are 38 and 39, showing that the presence of a pyridine, instead of a benzene ring, in the structure increases the trypanocidal activity, as in the pyrane derivatives shown above. The anti-trypanosomal activity of quinone 39 has been attributed to an increase of oxygen uptake indicating a significant redox cycling, while bromoquinones 36 and 37 inhibit overall oxygen uptake. On the other hand, compound 38, which is highly active in culture growth, produces neither overall respiration inhibition nor redox cycling. Considering that quinones are good electron acceptors, a possible relationship between the electron affinity (EA), electronegativity () and electrophilicity () of structurally


O


O

O

153

O

Br

N O

O

Br

O

O 36

O

N

O

O

37

O

38

Trypanocidal

39

Compounds

Activity

36

37

38

39

ICkc50 (μM)*

2.8

2.4

2.3

1.1


Fig. (9). Effect of nor--lapachone derivatives upon culture growth in T. cruzi epimastigote form. O

O

O

O

O

O

O

I

O

40

N3

O

41

42 Compounds


40

41

42

ED50 /24 h (μM)*

> 4800

158.1

179.3


Fig. (10). Trypanocidal effect nor--lapachone and its derivatives on bloodstream trypomastigotes of T. cruzi. O

O OH

O

O

Lapachol

ICkc50 (μM)*

OH

OH

O

43


O OH

O

44

Compounds lapachol

43

44

31.3

> 100

35.2


Fig. (11). Effect of lapachol and derivatives upon culture growth in T. cruzi epimastigote form.

related norlapachones with their trypanocidal activity has been recently described. Even though a limited number of compounds were used, the trend is very consistent, indicating that the greatest values of these parameters are obtained for the more active quinones, providing a new insight for the design of new drugs to be used in the treatment of Chagas disease [102].

De Castro et al. [103,104], have synthesized several of this nor--lapachone derivatives and the best compounds for trypanocidal study are quinones 41 and 42 (Fig. 10). 3.3. Lapachol´s Related Compounds Following the structural modifications of natural naphthoquinones and in the search of more active compounds or


O

Salas et al.

O OCH3

O OH

O 45

O OH

O

O

46

47

Trypanocidal

O

O 48

Compounds

Activity

45

46

47

48

ED50 /24 h (μM)

164.8

1280.2

330.7

420.7


Fig. (12). Trypanocidal effect of lapachol derivatives and analogs on bloodstream trypomastigotes of T. cruzi. O R1

O

O

O

R2

R2 O

R1

O

R

S

O

49a R = H b R = ET c R = CHMe2

50a R1= H; R2 = CHMe2 b R1= OMe; R2 = H

% inhibition*

51a R1= OMe; R2 = H b R1= H; R2 = NO2

Compounds


O

49a

49b

49c

50a

50b

51a

51b

100

94

94

88

52

26

54

* % values corresponding to culture growth inhibition at 50 μg/mL concentration.

Fig. (13). Trypanocidal effect of some furane and thiophenquinones on bloodstream trypomastigotes of T. cruzi.

with new biological properties, lapachol derivatives have been synthesized by means of several classic organic reactions looking for more active compounds or with new biological properties [89,116-121]. Tapia et al. demonstrated that although lapachol derivatives are not more active than - and -lapachones analogs, there are some compounds with trypanocidal effect, for example lapachol 1 and quinones 43 and 44 (Fig. 11), which show ICkc50 values of 10030 μM, when tested on the growth of Tulahuén strain of T. cruzi [68]. Pinto et al. have studied the trypanocidal behavior of several lapachol derivatives in banked blood for Chagas´ disease and the assays were all performed with trypomastigote forms in the presence of blood. Lapachol 1 and quinones 45, 47 and 48 displayed similar activities, which were somewhat higher than that of crystal violet, whereas norlapachol 46, was less active than lapachol [81]. The substitution of a hydroxy group in the original lapachol by methoxy in 45 led to a 2.5-fold increase in the trypanocidal activity. C-Allyl-lawsone 47 underwent a chemical transformation that led to compounds with trypanocidal activity similar to lapachol [99,122,123].

3.4. Other Quinones with Trypanocidal Activity In the search for new trypanocidal agents, different structural modifications of natural naphthoquinones have been realized in order to obtain several series of new heterocyclic derivatives. In the first attempts for the preparation of heterocyclic quinones, Goulart et al. studied the antiparasitic activities of some furane and thiophenquinones and their correlation with redox potential [124]. The results indicate that compounds 49-51 (Fig. 13), were able to eliminate the infective trypomastigote form of T. cruzi, Y strain, present in blood infected mice at 50 μg/mL concentration. o-Quinone were the most active compounds of the series, in relation to its p-quinone isomers, and this is in agreement with the results shown in this paper. Some indazolylquinones (Fig. 14) were screened against T. cruzi epimastigotes Tulahuén strains, some of them (quinone 53 and 56) as active as benznidazole. Among all the amide derivatives tested in this study, 54 and 57 were the least active compounds. Starting compounds for the synthesis of the benznidazole derivatives 52 and 55 had a moderate trypanocidal effect [125].


O


O

H3C

O

H3C

H3C

N N H

H3C

N

N

N

H3C

O

O

O

53

54

O

O

O

N

O N CH2C N

N

N H

N O

55

O CH2C NHCH2CH2OH

N

H3C

CH2COOCH3

52

O

155

O

N

CH2COOCH3

56

O 57 Compounds


52

53

54

55

56

57

% inhibition at 50μM*

97

97

35

80

98

41

* % values corresponding to culture growth inhibition at 50 μM concentration.

Fig. (14). Trypanocidal effect of indazolylquinones upon culture growth in T. cruzi epimastigote form.

Angular heterocyclic quinones from quinolines were synthesized and tested for trypanocidal activity (Fig. 15) [126]. All the compounds screened were active in the inhibition of growth of T. cruzi culture, although the most active compound was quinone 62 (ICkc50 = 6.8 μM). It was also observed that compounds with a tetracyclic system and two nitrogen atoms showed higher trypanocidal effect. Among these were compounds 60 and 61, which had ICkc50 values around 10-17 μM. On the other hand, it is noteworthy the difference between 62 and 63, since compound 63 was less active than 62 probably because 62 is more lipophilic due to the number and position of methyl group on the aromatic ring. Finally, some natural compounds containing a quinone and a drimane sesquiterpene skeleton, such as entcyclozonarone (+)-64, show a wide range of important bioactivities and have been used as model for new synthetic compounds with the same structural combined features, as the structures shown in Fig. 16 [127]. The trypanocidal study of these quinones on the growth of T. cruzi epimastigotes, showed that compound 65 is roughly 10 times more active, and compound 68 is about twice more active than nifurtimox and benznidazole. The common structural feature in all these compounds is the presence of a 2,3-unsubstituted naphthoquinone moiety. Compound 66 was about 5 times less active, compound 69 resulted about 7 times less active and compound 67 was some 10 times less active than the reference substances. These compounds are 1,4-benzoquinones, 2,3dimethyl 1,4-naphthoquinones, or substituted anthraquinones. Trypanocidal activity was demonstrated to involve the generation of oxygenated intracellular species; thus it must be related to the compound lipophilicity (related with the size and polarity) and its reduction potential (related to the electron-withdrawing ability) [124]. 1,4-Naphtho-quinones can also be considered as subversive substrates of trypanothione reductase [128-130]. For these compounds, it

was observed that in order to have an active compound, a 2,3-unsubstituted naphthoquinone is required, and that an increase in molecular size or substitution leads to a lower bioactivity. Another possible explanation for the observed behavior of the different activities of the compounds in Fig. (13) concerns their electron-withdrawing ability, which is directly related to the experimental half-wave potentials. According to the literature, 2,3-dimethyl-1,4-naphthoquinone and 9,10-anthraquinone have similar potentials (around 0.85V). On the other hand, 1,4-naphthoquinone has a rather larger potential (of about -0.63 V). Consequently, compound 65 is the best oxidant in this series, and also the most active compound. 3.5. Quantitative Structure-Activity Relationships It has been proposed that the production of reactive oxygen radicals through redox cycling is the mechanism by which naphthoquinones exhibit their trypanocidal activity. This mechanism of action requires bioreduction of quinones as the first activating step; this is why the electrochemical behavior of many quinones has been studied. Therefore, the electrochemical properties of species generated in the course of redox cyclic conversions are important for a better understanding of their biological activity. Goulart et al. have studied the correlation of trypanocidal activity of naphthoquinones with their redox potential in aprotic medium, using Hg as the working electrode. Although there is no linear correlation between the redox potential of the naphthoquinones, those compounds presenting first reduction potentials more positive than – 0.72 V vs. SCE probably will have trypanocidal activity, especially if they are o-naphthoquinones [124]. It is known that naphthoquinones are reduced by Trypanothione Reductase (TR), generating reactive oxygen species


Salas et al.

Ph O

O

O

H3C

O

S

H3C

H3C

N

CH3

N

H3C

H3C

N

O

O

58

59

CH3

H3C

N

CH3

O 60

Ph R1

O

N

O

O

Cl

H3C N R2

CH3

Cl Cl

Cl

H3C

N

O

O

61a R1= H; R2= CH3 b R1= CH3; R2=H

62

N

CH3 CH3

CH3

O 63

Trypanocidal

Compounds

Activity ICkc50 (μM)*

58

59

60

61a

61b

62

63

15.21

23.11

13.18

10.39

17.1

6.83

16.29


Fig. (15). Effect of quinolinequinones upon culture growth in T. cruzi epimastigote form. CH3 O

O

O

O

H

CH3

O

O

H 64

65

66 O

O

O O

O

O

O O O O

67

68

69

Trypanocidal

Compounds

Activity

64

65

66

67

68

69

ICkc50 (μM)*

-

0.7

40

84.4

4.9

60.6


Fig. (16). Effect of sesquiterpenequinones and related compounds upon culture growth in T. cruzi epimastigote form.


through redox cycle via reaction of the reduced quinone with molecular oxygen. Enzymatic and antitrypanosomal studies have revealed that several naphthoquinones derivatives with strong trypanocidal activity were among the most effective TR inhibitors, suggesting that naphthoquinone reduction by parasitic flavoenzymes is a promising strategy for the development of new trypanocidal drugs [128-130]. Furthermore, docking studies performed to elucidate the interaction mechanism of the quinones with the trypanothione reductase (TR) enzymes and glutathione reductase (GR) enzymes, showed that all quinones stay in the same region in the TR enzyme, a result that could be explored to design selective inhibitors of TR [119,131].

Current Medicinal Chemistry, 2011 Vol. 18, No. 1 [2]

[3]

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Theoretical calculations and artificial neural networks (ANN) were used to predict the trypanocidal activity of naphthoquinone compounds. Electronic and structural properties are important factors in determining the interaction between quinone compounds with trypanocidal activity and their biological receptors. ANN models could be useful in the design of novel trypanocidal quinones having improved potency [132].

[7]

Quantitative structure activity relationship (QSAR-2D) studies indicate that the best trypanocidal activity is obtained with quinone molecules in the semiquinone electronic state, possessing high negative value of EHOMO, high negative charge in the oxygen atoms of the carbonyl groups, high positive charge in the carbon atom of one of the carbonyl moieties and high electronegativity. In a complementary way, the QSAR-3D study indicates that the electrostatic field correlates with the trypanocidal activity [94].

[10]

[8]

[9]

[11]

[12] [13]

4. CONCLUSIONS In conclusion, a number of factors limit the utility of the existing drugs for Chagas disease: primarily because of their low efficacy (mostly upon chronic patients), poor activity against many T. cruzi isolates circulating in different geographic areas and considerable side effects. Additionally, in the past few decades, few compounds have moved to clinical trials due to the minimal investments allocated to this area (as well as to other neglected diseases) and the lack of standardized protocols for drug screening. In addition, the identification of new trypanocidal candidates that could enter clinical studies requires integrated partnerships and interdisciplinary networks that involve expertise in a variety of fields such as molecular and cellular biology, chemistry and biochemistry, pharmacology and toxicology. Thus, with the advent of genomics, rapid DNA sequencing, bioinformatics, proteomics, combinatorial chemistry and automated highthroughput screening, extensive knowledge has accumulated that provides new insight toward the discovery of more selective and successful compounds. ACKNOWLEDGEMENTS

[14]

[15] [16] [17]

[18]

[19]

[20]

We are grateful to FONDECYT (Research Grants 1020874, 11085027, 1060952 and 1090078) and Anillos ACT112, for financial support. [21]

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Dubner, S.; Schapachnik, E.; Riera, A.R.; Valero, E. Chagas disease: state-of-the-art of diagnosis and management. Cardiol. J., 2008, 15, 493-504. Rocha, M.O.; Nunes, M.C.; Ribeiro, A.L. Morbidity and prognostic factors in chronic chagasic cardiopathy. Mem. Inst. Oswaldo Cruz, 2009, 104 (Suppl 1), 159-166. Wilkinson, S.R.; Kelly, J.M. Trypanocidal drugs: mechanisms, resistance and new targets. Expert Rev. Mol. Med., 2009, 11, 1-31. Schmunis, G.A.; Yadon, Z.E. Chagas disease: A Latin American health problem becoming a world health problem. Acta Trop. (In press). Dobarro, D.; Gomez-Rubin, C.; Sanchez-Recalde, A.; Olias, F.; Bret-Zurita, M.; Cuesta-Lopez, E.; Robles-Marhuenda, A.; FraileVicente, J.M.; Pano-Pardo, J.R.; Lopez-Sendon, J. Chagas' heart disease in Europe: an emergent disease? J. Cardiovasc. Med., 2008, 9, 1263-1267. Schmunis, G.A. Epidemiology of Chagas disease in non-endemic countries: the role of international migration. Mem. Inst. Oswaldo Cruz, 2007, 102 (Suppl 1), 75-85. Aufderheide, A.C.; Salo, W.; Madden, M.; Streitz, J.; Buikstra, J.; Guhl, F.; Arriaza, B.; Renier, C.; Wittmers, L.E.Jr.; Fornaciari, G.; Allison, M. A. 9,000-year record of Chagas disease. Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 2034-2039. Marin-Neto, J.A.; Rassi, A. Jr.; Update on Chagas heart disease on the first centenary of its discovery. Rev. Esp. Cardiol., 2009, 62,1211-1216. Tanowitz, H.B.; Machado, F.S.; Jelicks, L.A.; Shirani, J.; de Carvalho, A.C.; Spray, D.C.; Factor, S.M.; Kirchhoff, L.V.; Weiss, L.M. Perspectives on Trypanosoma cruzi-induced heart disease (Chagas disease). Prog. Cardiovasc. Dis. 2009, 51, 524-539. Bilate, A.M.; Cunha-Neto, E. Chagas disease cardiomyopathy: current concepts of an old disease. Rev. Inst. Med. Trop. Sao Paulo, 2008, 50, 67-74. Teixeira, A.R,.L.; Nitz, N.; Guimaro, M.C.; Gomes, C.; SantosBuch, C.A. Chagas disease. Postgrad. Med. J., 2006, 82, 788-798. Faundez, M.; Pino, L.; Letelier, P.; Ortiz, C.; Lopez, R.; Seguel, C.; Ferreira, J.; Pavani, M.; Morello, A.; Maya, J.D. Buthionine sulfoximine increases the toxicity of nifurtimox and benznidazole to Trypanosoma cruzi. Antimicrob. Agents Chemother., 2005, 49, 126-130. Maya, J.D.; Cassels, B.K.; Iturriaga-Vasquez, P.; Ferreira, J.; Faundez, M.; Galanti, N.; Ferreira, A.; Morello, A. Mode of action of natural and synthetic drugs against Trypanosoma cruzi and their interaction with the mammalian host. Comp. Biochem. Physio.l A Mol. Integr. Physiol., 2007, 146, 601-620. Burleigh, B.A.; Woolsey, A.M. Cell signalling and Trypanosoma cruzi invasion. Cell. Microbiol., 2002, 4, 701-711. Rassi, A. Jr.; Rassi, A.; Marin-Neto, J.A. Chagas disease. Lancet. 2010, 375, 1388-1402. Bastos, C.J.; Aras, R.; Mota, G.; Reis, F.; Dias, J.P.; de Jesus, R.S.; Freire, M.S.; de Araújo, E.G.; Prazeres, J.; Grassi, M.F. Clinical outcomes of thirteen patients with acute Chagas disease acquired through oral transmission from two urban outbreaks in northeastern Brazil. PLoS Negl. Trop. Dis., 2010, 6, e711. Soares, M.B.; Santos, R.R. Current status and perspectives of cell therapy in Chagas disease. Mem Inst Oswaldo Cruz, 2009, 104 (Suppl 1), 325-332. Lopez-Muñoz, R.; Faundez, M.; Klein, S.; Escanilla, S.; Torres, G.; Lee-Liu, D.; Ferreira, J.; Kemmerling, U.; Orellana, M.; Morello, A.; Ferreira, A.; Maya, J.D. Trypanosoma cruzi: In vitro effect of aspirin with nifurtimox and benznidazole. Exp. Parasitol., 2010, 124, 167-171. Urbina, J.A.; Concepcion, J.L.; Caldera, A.; Payares, G.; Sanoja, C.; Otomo, T.; Hiyoshi, H. In vitro and in vivo activities of E5700 and ER-119884, two novel orally active squalene synthase inhibitors, against Trypanosoma cruzi. Antimicrob. Agents Chemother., 2004, 48, 2379-2387. Urbina, J.A.; Payares, G.; Sanoja, C.; Lira, R.; Romanha, A.J. In vitro and in vivo activities of ravuconazole on Trypanosoma cruzi, the causative agent of Chagas disease. Int. J. Antimicrob. Agents, 2003, 21, 27-38.

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Received: September 15, 2010

Revised: November 13, 2010

Accepted: November 15, 2010


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