Multi-Target Antitubercular Drugs

13 downloads 0 Views 405KB Size Report
2018 Bentham Science Publishers. Multi-Target Antitubercular Drugs. Jessika de Oliveira Viana1, Hamilton Mitsugu Ishiki2, Marcus Tullius Scotti1 and Luciana ...
Send Orders for Reprints to [email protected] Current Topics in Medicinal Chemistry, 2018, 18, 1-8

1

REVIEW ARTICLE

Multi-Target Antitubercular Drugs Jessika de Oliveira Viana1, Hamilton Mitsugu Ishiki2, Marcus Tullius Scotti1 and Luciana Scotti1,3,* 1

Cheminformatics Laboratory- Postgraduate Program in Natural Products and Synthetic Bioactive, Federal University of Paraíba, Campus I, 58051-900,João Pessoa-PB, Brazil; 2University of Oeste Paulista, 19050-900 - Presidente Prudente, SP – Brazil; 3Teaching and Research Management - University Hospital, Federal University of Paraíba, Campus I, 58051-900, João Pessoa-PB, Brazil

ARTICLE HISTORY Received: December 01, 2017 Revised: March 13, 2018 Accepted: May 17, 2018 DOI: 10.2174/1568026618666180528124414

Abstract: Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis, which has high levels of mortality worldwide and has already gained resistance to first- and second-line drugs. The study by new chemical entities with promising activities becomes paramount to broaden the therapeutic strategies in the cure of the patients affected with this disease. In this context, in this review we report the discovery of 3 classes of compounds that can simultaneously interact with more than one target of Mycobacterium tuberculosis.

Keywords: Anti tuberculosis drugs, tuberculosis, multi-target drugs, targeting, inhibition. 1. INTRODUCTION Antimicrobial resistance is a major global concern. Strains of tuberculosis (TB) resistant to rifampicin and other drugs challenge patient survival and public health. The World Health Organization (WHO) [1] has issued treatment guidelines for drug-resistant tuberculosis since 1997, and last updated these guidelines in 2016 based on assessments of patient data in both published and unpublished studies. As the first choice for patients assailed by multiple drug resistant or rifampicin resistant (MDR/RR) strains, WHO recommends a standardized treatment regimen of from 9 to 12 months. Currently, in addition to the growing problem of neglected diseases, AIDS co-infection has become prevalent in several patients with tuberculosis; there are around 1.5 million tuberculosis-related deaths globally, and up to 400,000 co-infections with HIV [2]. Linked to this, the emergence of drug resistant cases in tuberculosis treatment has become a frequent issue. The need for new and more potent, selective compounds is crucial. To patients with tuberculosis, the most commonly administered drugs are: Isoniazid, Rifampicin, Pyrazinamide, Streptomycin, Ethambutol, Ethionamide, Kanamycin, Cycloserine, Capreomycin and Ofloxacin (Fig. 1) [3,4]. Mycobacteria are characterized as slow-growing bacillus having a cell wall composed of highly lipophilic mycolic acids. The nature of this cell wall is of most importance to the development of new candidates for anti-tuberculosis (anti-TB) drugs [5]. Mycobacterium tuberculosis is an intracellular pathogen highly adapted to its natural host: the hu*Address correspondence to this author at the Health Sciences Center, Federal University of Paraíba, Campus I, 58051-970, João Pessoa-PB, Brazil; Fax 55-83-3291-1528; E-mail: [email protected]

1568-0266/18 $58.00+.00

man. Its main host cell reservoir is the mononuclear phagocyte (monocytes and macrophages). Morphologically, the microorganism is characterized as a straight or curved bacillus, ranging in size from (0.2 to 0.6) x (1 to 10) micrometers, immobile, without pores, non-encapsulated, non-toxin producing, and capable of surviving within phagocytic cells. It is characterized as a restricted aerobic intracellular pathogen. Its cell wall, consisting mainly of mycolic acids forms a hydrophobic barrier that confers resistance to both desiccation and discoloration by alcohol or acid [6]. During the infection process, the mycobacterium uses its lipases and phospholipases to hydrolyze host cell lipids and ensure extended survival. By associating tuberculosis with several other diseases, which are considered multifactorial, the administration of numerous drugs can lead to adverse mechanisms in patients, so that the treatment does not achieve its desired effect, which may also lead to bacterial resistance [7,8,9,10]. By means of this, a strategy that has been elaborated in an effective way is the development of multi-target drugs, characterized by a single molecule, or ligand, that is able to interact with two or more receptors, being able to act synergistically in several targets [11]. Together with computer-assisted drug design, molecular screening studies have been reported as discovering possible protein target interactions for given diseases, and as characterizing potential inhibitors [12]. Such interactions provide a better therapeutic profile, since by using in silico methods as a tool, they can modulate structures to maximize pharmacological effects [13,14,15]. Two methods are currently used to identify multi-target inhibitors [16,17,18]. In one screening method, the pharmacophore is used at the target binding sites, (or known inhibitors can be used), and possible multitarget binders can be used as well. In another screening method, pharmacophores of the protease-linker complex are used. In either of these approaches it is necessary to under© 2018 Bentham Science Publishers

2 Current Topics in Medicinal Chemistry, 2018, Vol. 18, No. 00

de Oliveira Viana et al. O

H2N

OH

HN

HN

HHO N

N

N

O

NH H2N

NH2

NH2

O

NH2

N

O

Cycloserine

Pyrazinamide

Ethionamide S

NH

N

H N

HN N H

O

NH2

O

O

H2N

NH

Capreomicin O

O

NH2

O

OH Rifampicin

O O

O O HN

N

NH2

OH

O

N OH

O

Isoniazid

Ofloxacin

F N

OH HO

N

N

OH

N

HO HN

N

O NH2

O HO

HN

NH

O

O

OH

HN NH

OH

H2N

OH

OH

OH HO

O

OH

HO

O

HO

H2N

H2N

O

OH

O

NH2 O

H2N

NH

O

Kanamicin

HO

OH

OH

Streptomicin

H N

HO

N H

Ethambutol

Fig. (1). Commonly administered drugs in the treatment of tuberculosis.

stand the interaction of the molecular elements of the ligands and the protein targets under study. Multi-target activity studies have shown to be more promising because they are more efficient, safer, simpler to administer, and can bypass resistance mutations in target proteins [19]. Ideally, a multi-target drug must effectively interact with the targets while reducing interaction risks or interfering with the patient's healthy state [20]. 2. TARGETS 2.1. DNA Gyrase Topoisomerase can exist in two types; this depends on the catalysis of a single or both strands of DNA which can relax the DNA winding. DNA gyrase (EC 5.99.1.3, DNA topoisomerase) is a type of topoisomerase that unlike the others, catalyzes DNA supercoiling by means of a reaction dependent on the hydrolysis of ATP [21,22]. The enzymeprotein DNA gyrase is being considered as a good target for tuberculosis treatment. Its structure is hetero-tetrameric based, with two A subunits, and two B subunits, known as A2B2 [23,24]. The A subunit is considered a fluoroquinolone target. Current studies have reported mycobacterial resistance to fluoroquinolones generated by means of a point mutation in the GyrA gene.

The B subunit is a target for Novobiocin, an aminocoumarin derivative. Genetically, the B subunit has been extensively studied, and it has been shown in Mycobacterium tuberculosis to be a target of bactericidal drugs, exerting viable phenotypic effects for an anti-tuberculosis target [25]. GyrB presents several attractive qualities for a lead target. Principally, since mycobacteria do not have alternative mechanisms to perform the same protein functions, its inhibition leads to significant cell death. In studies by Chopra (2012) [26], GyrB genes were sequenced and demonstrated 99.9% homology, with almost no variance in their DNA sequences, this suggests that for anti-tuberculosis activity the B subunit may be a promising target. 2.2. FadD32 Also referred to as fatty acyl-CoA synthetase (FACS), the FadD32 (EC.6.2.1) protein is one of the thirty-four FadD proteins present in Mycobacterium tuberculosis. FadD32 is an enzyme which acts on mycolic acid biosynthesis which is essential for bacterial growth and development. As shown in crystalline structure studies, FadD32 contains two globular domains connected by a flexible ligand. ATP coupling at an interface between the C and N-terminal domains induces conformational change in the enzyme. In in vitro biochemical assays it has been seen that inhibition of this enzyme may

Multi-Target Antitubercular Drugs

Current Topics in Medicinal Chemistry, 2018, Vol. 18, No. 00

3

decrease M. tuberculosis growth within the macrophage [27].

precursor of arabinogalactan and lipoarabinomannan (LAM) synthesis in the mycobacterium cell wall [44].

The ANL superfamily of adenylating enzymes, characterized by adenylate formation, includes acyl and aryl-CoA synthetase, with adenylation domains of non-ribosomal peptides (NRPS), and firefly luciferases. Such assays are essential to understand their mechanisms and design inhibitors with anti-tuberculosis activity. These enzymes are characterized by having two catalytic forms: one enters a reaction that forms adenylate and leads to the formation of acyl-AMP by means of a carboxylate substrate; another involves formation of a thioester and leads to the formation of acyl-CoA by means of acyl-AMP/CoA, or formation of Acyl-ACP by means of acyl-AMP/ACP [28]. The second reaction is not catalyzed because insertion impedes rotation of C-terminal domains [29].

The crystalline structural form of the enzyme DprE1 has been described as linked to compounds BTZ043 and TCA1, two benzothiazinone derivatives [45,46]. DprE1 protein structures present in M. smegmatis and M. tuberculosis share a homology of 83% [45, 47]. Binding of the compound BTZ as a substrate converts the enzyme into its reduced form by a nitro-reduction mechanism forming a nitro-derivative on the DprE1active site [47,48,49]. Enzymatic reaction depends on the presence of NADP; the enzyme is essential for cell survival and growth; and a possible target for therapeutic studies against tuberculosis [48,50]. DprE1 catalyzes the conversion of DPR to DPX, a FAD-dependent oxidation catalysis, where flavin is reduced to FADH2 and re-oxidized. In certain studies, it has been reported that compounds containing nitro-substituents are converted into amino groups by DprE1, which covalently react with the cysteine portion inactivating the enzyme [51].

In similar studies of DNA base pair FadD sequences, two functions were identified: 1) the existence of many FadD proteins with FACS activity; 2) a smaller set of FadD proteins, such as FadD32 with only the first reaction catalytic activity [30]. The activity of FadD32 is based on activating meromycolic acid (C50-C60) condensed by Pks13 with a C22-C26 fatty acid, to form mycolic acid. 2.3. MtFtsZ The FtsZ (EC 3.4.24) protein is a tubulin homologous enzyme which participates in the process of bacterial cell division. Ubiquitous in the cell, it plays an essential role in the cytokinesis of bacteria. The reaction takes place by in the presence of GTP, with polymerization of the FtsZ protein at a certain point in the inner membrane, developing until the formation of a helical structure [31,32,33,34], called the Z ring [35]. With the aid of other cell division proteins, the Zring contracts before septum formation [36]. The formed septum is then regulated by other stabilizing factors, such as ZapA, ZipA, FtsA, and destabilizers, such as SulA, EzrA and MinCD [37]. Inhibitors of the enzyme interrupt septum formation, making it a promising anti-mycobacterial, and specifically anti-tuberculosis target [38,39,40,41]. 2.4. DprE1 The interruption of cell wall synthesis is considered a new target for drug development. The microorganism Mycobacterium tuberculosis contains in its cell wall, formed by layers of external lipids: mycolic acid, polysaccharides (arabinogalactan), peptidoglycan, plasma membrane, lipoarabinomannan (LAM) and mannoside phosphatidylinositol. Among these constituents, the arabinogalactans are the precursors of cell wall synthesis [42]. In genetic studies of resistant Mycobacterium tuberculosis species enzymatic studies have identified the enzyme decaprenylphospho-β-D-ribofuranose 2-oxidase (DprE1 (EC 1.1.98.3)), a flavo-enzime required for the synthesis of the M. tuberculosis cell wall [43]. DprE1 acts together with DprE2 to catalyze the epimerization of decaprenylphosphoribose (DPR) into decaprenylphospho-D-arabinofuranose (DPA) through an intermediate formation of decaprenylphosphoryl-2-keto-ribose (DPX); the latter, being the only

2.5. Mur Ligase Proteins belonging to the Mur ligase family share both structural and functional correlations, which may determine common action mechanisms [52] as seen in the several structural characterizations reported in literature [53]. The function of the ligases MurC, MurD, MurE (EC 6.3.1.1, Lcysteine:1D-myo-inositol 2-amino-2-deoxy-α-Dglucopyranoside ligase), and MurF is to catalyze nonribosomal peptide bonds for the addition of peptide moieties in the formation of peptidoglycan (PG) [54,55,56]. For this reason, they have become a promising target in antituberculosis activity [57,58]. In correlation studies between Escherichia coli and Mycobacterium tuberculosis, Mur ligase showed 37% structural similarity, which is low and difficult to determine by modeling. The structures of Mur ligases involve a monomeric protein with three catalytic domains: each varying between ligases such that the UDP portion remains correctly distanced from the active site. MurE and MurF contain this conserved domain, which shares a similarity of nucleotide binding domains, involves ATP coupling, substrate activation and resembles the Rossmann fold. In the Mur ligase family, it is a conserved domain where amino acid binding occurs [59]. These ATP-dependent Mur ligase proteins play an important role in cell-like biosynthesis having high specificity to their substrate. MurE is encoded as a single copy in the TM genome and is also reported in other microorganisms [60]. The MurC biochemical pathway in peptidoglycan (PG) biosynthesis begins with conversion of UDP-GlcNAc (available in the bacterial cytoplasm) to UDP-MurNAc by enolpyruvyl transferase-MurA, and a flavin-dependent reductase MurB. Afterwards, the MurC protein adds the amino acid LAla to form UDP-MurNAc-L-Ala [61]. The MurD protein catalyzes the binding of an amide bond between the D-Glu and UDP-MurNAc-L-Ala to form UDP-MurNAc-LAla-DGlu. Studies have shown that the specificity of MurD classifies it as a promising target for antibacterial activity [62], where it is denoted as the step that guarantees the relative PG thickness in mycobacteria [63]. The MurE protein is responsible for the addition of a third residue to the peptide, being

4 Current Topics in Medicinal Chemistry, 2018, Vol. 18, No. 00

the only protein in its family that is specific between bacteria. The third substrate insertion is a characteristic of the specificity because it is involved in crosslinking the glycan chain and maintaining PG integrity in the mycobacteria. If this integrity is not maintained, morphological PG changes can trigger cellular lysis [64]. MurF adds the dipeptide DAla-D-Ala to UDP-MurNAc-L-Ala-D-Glu-(mA2pm/L-lys) to form the cytoplasmic PG precursor: UDP-MurNAc-LAla-D-Glu-(mA2pm/L-lys)-D-Ala-D-Ala [65]. This dipeptide is an essential factor for PG formation, such that its binding energizes the binding of the glycan chain [66]. 2.6. MmpL3 The mmpL3 protein functions as internal membrane transporter, exporting mycolic acids to the peri-plasmic space in the form of trehalose monomicolate (TMM). This glycolipid acts as an acid donor in formation of the mycobacterium outer membrane, commonly known as the mycomembrane [67, 68, 69]. 2.7. MenA and MenG The biosynthesis of menaquinone has been studied. Its biochemistry involves formation of compounds using chorismate. Recent studies have reported the use of menaquinone as a possible target for mycobacterial inhibitors. Menaquinone proteins are typed as: MenF, MenH, MenC, MenE, MenI, MenB, MenA and MenG [70, 71], all of which exist in bacteria yet are not present in humans, making them even more attractive as a target [72]. Studies have reported significant MenA (EC 2.5.1.74, 4-dihydroxy-2-naphthoate polyprenyl transferase) inhibition. Its synthetic route involves catalyzes the isoprenylation of 1, 4-dihydroxy-2naphthoic acid by long chain isoprenoid diphosphates, making MenA a interest target in M. tuberculosis drug [73, 74]. Among the types of proteins involved in the synthesis of menaquinones, MenG (EC 2.1.1.163, demethylmenaquinone methyltransferase) has become a possible target in the search for new anti-tb agents. Its synthesis involves Sadenosylmethionine (SAM) -dependent methylation of demethylmenaquinone (the product of the MenA reaction) [75, 76].

de Oliveira Viana et al.

hydroxycinnamic acid-containing lactones, consisting of a benzene ring fused to a lactone [79]. According to their chemical structure, coumarins can be grouped into 4 types: simple, furanocoumarins, pyranocoumarins and lactone ring substituted coumarins [80]. Coumarins are obtained synthetically or from secondary plant and fungal metabolites. As to identification of coumarin as a potential multi-target candidate, studies have been conducted involving coumarin activity in several targets. In these studies, it was found that Novobiocin, an aminocoumarin acts by inhibiting one of the bacterial topoisomerases: DNA gyrase, acting potently on the Gyrase B subunit (GyrB) in the nanomolar range of (7-15 nM) [81]. In addition to identification of this target, Kawate et al. (2013) [82] identified a new mechanism of action for coumarin candidates: FadD32. These coumarin derivatives (Fig. 2A) presented potent anti-tuberculosis activity, with IC90 values between 2 µM and 0.5 µM. Structural optimizations were performed that increased the anti-mycobacterial potency in mice (0.4 µM). Stanley et al. (2013) [83] reported identification of inhibitory coumarins acting directly on the FadD32 protein in Mycobacterium tuberculosis (Fig. 2B), blocking bacterial replication in vitro and in vivo with MIC values of between 5.6 µM and 0.24 µM. Sridevi and coworkers (2017) [84], studying new coumarin analogs (Fig. 2C) reported on their effects on FtsZ, a target for Mycobacterium tuberculosis and M. smegmatis, where they inhibited the polymerization and GTPase activity of the protein. Docking studies demonstrated strong interaction with the GTP binding site at the G103 residue, providing a possible binding site for coumarin derivatives in Mycobacterium tuberculosis. Other compounds containing a coumarin moiety with potent activity (Fig. 2D) have been reported by Shaikh et al. (2016) [85] citing action on the enzyme DprE1 of M. tuberculosis. The study results were both comparable and more promising than those reported in the literature, with MIC values of between 1.8 and 4 µg/mL. The docking analysis showed positive ligand-protein interactions which characterize coumarin as a promising multi-target lead in the study of anti-tuberculosis activity.

NH

2.8 ATP Synthase ATP synthase (EC 3.6.1.3) has an essential function within the cells of providing ATP by means oxidative phosphorylation [77]. In this process, the coupling of protons occurs in the mitochondrial ridges, periplasmic space of the matrix, and the bacterial cytoplasm. Genetic studies have shown that both in prokaryotes and eukaryotes the region is evolutionarily conserved. Computational blockade studies of ATP synthase activity have been performed and it was found that the compound R207910 blocks hydrogen transfer between subunits A and C of the enzyme, inhibiting ATP production [78]. 3. MULTI-TARGET STUDIES 3.1. Coumarin Coumarins, also known as α-benzopyrones, have their chemical structure based on a large family of o-

N O O

O

O

N H

O A

C

NH2 N O O O

O

B

O

O D

N N N

Fig. (2). Structure of coumarin compounds reported in the literature, being likely multi-target inhibitors. A and B) FadD32 inhibitors; C) FtsZ inhibitor of Mycobacterium tuberculosis; D) Mycobacterium tuberculosis DprE1 inhibitor.

3.2. Quinolones

Multi-Target Antitubercular Drugs

Current Topics in Medicinal Chemistry, 2018, Vol. 18, No. 00

The quinolines are a group of alkaloid derived antimicrobials with structure similarity in the quinolone nucleus. Following modifications at the quinolone nucleus by the addition of various substituents they are widely employed therapeutically. Several studies have reported the activity of quinolone compounds on DNA gyrase in Mycobacterium tuberculosis, one of the proteins belonging to the topoisomerases [86,87,88]. Minovski et al. (2012) [89] reported a combinatorial library study of 53,871 analogs of 6-fluoroquinolone (Fig. 3A), tested for prediction of biological activity and constructing chemometric studies with model construction and molecular docking. The study determined that among the fluoroquinolones used in the analyses, moxifloxacin, ofloxacin, and ciprofloxacin were the most promising, as led by ciprofloxacin. The study allowed the design of novel quinolone candidates with Mycobacterium tuberculosis Gyrase A activity. Another study, conducted by Guzman et al. (2011) [90] evaluated the activity of quinolone derivatives inhibiting MurE ligase in Mycobacterium tuberculosis, M. bovis and M. smegmatis. Inhibition in M. tuberculosis occurred at doses of 15.3 - 84 µM, with anti-mycobacterial activity (Fig. 3B). The same molecular modeling studies were done to predict the structure of MurE with quinolone where weak interactions were observed. In the rational design of new derivatives, such weak interactions can be used to incorporate other substituents to promote better anti-TB activities. Guzman, in 2015 [91], reported the study of new tetrahydroisoquinoline derivatives (Fig. 3C) and elucidation of a possible pharmacophore in the ATP-dependent MurE enzyme of Mycobacterium tuberculosis. In this study, inhibition activity ranging from 71- 206 µM for M. tuberculosis and yielding 148 µM for the MurE enzyme alone was weaker than the reference drugs, yet the compounds exhibited possible pleiotropic activity mechanisms in mycobacteria. O

O

O

F

OH

N HO

N

N

N

O

B

A

5

nism of action involves interruption of the Mmpl3 enzyme. All of the organisms under study had mutations in the mmpl3 gene which suggests that the enzyme might be a good target for structural modifications using SQ109 ligands. In a study by Li et al. (2014) [94], inhibition of enzymes involved in biosynthesis of Menaquinone (MenA and MenG), in electron transport, and inhibition of ATP biosynthesis, under the action of SQ109 derivatives were reported (Fig. 4). These variants presented activity of up to 5x more potent than SQ109 as reported in the literature. The most potent activity (against M. tuberculosis) had an MIC of 0.020.05 µg/mL. The inhibition data for the enzymes MenA and MenG occurred in a compound with respective minimums of 4 and 5.7 µM. The multitarget action of these compounds is essential, and the study demonstrated a broad coupling of ligands, the potent anti-TB inhibitory action, a fall off of resistance rates, and a certain similarity between the administered drugs. H N N H

Fig. (4). Structure of the SQ109 group, likely multi-target inhibitor(s) of the Mmpl3, MenA and MenG, and ATP biosynthesis proteins.

CONCLUSION We report the first review of multitarget compounds with antituberculosis activity, bringing the activity of coumarins in the enzymes FadD32, MtFtsZ and DprE1; quinolones with activity on ATP-dependent MurE enzyme and DNA gyrase in subunits A and B; and the synthetic compound, SQ109, in the enzymes MenA and MenG, MmpL3 and ATP biosynthesis proteins. The development of multitarget studies has grown in recent years due to the reduction of financial costs and more pronounced therapeutic activity against diseases of multiple effects, being this one of the focuses of the pharmaceutical industry today. Therefore, investing in multitarget drug studies becomes one of the crucial points in the discovery by new promising agents against tuberculosis. CONSENT FOR PUBLICATION

I

Not applicable. CONFLICT OF INTEREST

NH O

O C

The authors declare no conflict of interest, financial or otherwise.

O

Fig. (3). Structure of the quinolones group reported in the literature, likely multi-target inhibitors. A). Inhibitor of Gyrase A; B and C). Inhibitors of Mycobacterium tuberculosis MurE.

3.3. SQ109 SQ109 is a small 1,2-ethylenediamine molecule that has gained attention as a possible drug candidate because it has a C10 isoprenoid side chain [92]. Tahlan 2012 [93], reported that SQ109 was studied to treat tuberculosis, where it was evidenced in genomic sequencing analyses that its mecha-

ACKNOWLEDGEMENTS We would like to thank the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes) for financial support. REFERENCES [1]

WHO, World Health Organization. Global Tuberculosis Report 2016.http://www.who.int/tb/publications/global_report/en/ (accessed July 15, 2017).

6 Current Topics in Medicinal Chemistry, 2018, Vol. 18, No. 00 [2] [3] [4] [5] [6]

[7] [8] [9] [10]

[11]

[12]

[13] [14] [15] [16] [17] [18]

[19] [20] [21] [22] [23] [24]

[25] [26]

Cragg, G.; Newman, D. Natural products and drug discovery and development: A history of success and continuing promise for the future. Planta Medica, 2014, 80, 703-723. WHO, World Health Organization. Global Tuberculosis Report 2014.http://www.who.int/tb/publications/global_report/en/ (accessed March 5, 2017). Barot, K.P.; Nikolova, S.; Ivanov, I.; Ghate, M.D. Antitubercular drug development: Current status and research strategies. Mini-Rev. Med. Chem., 2013, 13, 1664-1684. Campos, H.C. Etiopatogenia da tuberculose e formas clínicas. Pulmão RJ, 2006, 15(1), 29-35. Ducati, R.G. Especificidade de substrato e mecanismo cinético da enzima fosforilase de nucleosídeos purínicos de Mycobacterium tuberculosis. PhD Thesis, Federal University of Rio Grande do Sul, March, 2009. Pierce, G. Should we clean up the reputation of “dirty drugs”? Can. J. Physiol. Pharmacol., 2012, 90, 1333-1334. Koeberle, A.; Werz, O. Multi-target approach for natural products in inflammation. Drug Discov. Today, 2014, 19, 1871-1882. Dias, K.S.T.; Viegas, C. Multi-Target Directed Drugs: A Modern Approach for Design of New Drugs for the treatment of Alzheimer’s Disease. Curr. Neuropharmacol., 2014, 12, 239-255. Pang, M.H.; Kim, Y.; Jung, K.W.; Cho, S.; Lee, D.H. Foundation review: A series of case studies: Practical methodology for identifying antinociceptive multi-target drugs. Drug Discov. Today, 2012, 17, 425-434. Agis-torres, A.; Söllhuber, M.; Fernandez, M.; Sanchez-Montero, J.M. Multi-Target-Directed Ligands and other Therapeutic Strategies in the Search of a Real Solution for Alzheimer’s Disease. Curr. Neuropharmacol., 2014, 12, 2-36. Jenwitheesuk, E.; Horst, J.A.; Rivas, K.L.; Voorhis, W.C.V.; Samudrala, R. Novel paradigms for drug discovery: computational multitarget screening. Trends in Pharmacol. Sci., 2008, 29(2), 6271. Koh, H.L.; Yau, W.P.; Ong, P.S.; Hegde, A. Current trends in modern pharmaceutical analysis for drug discovery. Drug Discov. Today, 2003, 8, 889-897. Clark, D.E. What has computer-aided molecular design ever done for drug discovery? Expert. Opin. Drug Discov., 2006, 1, 103-110. Cross, S.; Cruciani, G. Molecular fields in drug discovery: getting old or reaching maturity? Drug Discov. Today, 2010, 15, 23-32. Morphy, R.; Kay, C.; Rankovic, Z. From magic bullets to designed multiple ligands. Drug Discov. Today, 2004, 9, 641-651. Morphy, R.; Rankovic, Z. Designed multiple ligands. An emerging drug discovery paradigm. J. Med. Chem., 2005, 48, 6523-6543. Speck-Planche, A.; Kleandrova, V.V.; Luan, F.; Cordeiro, M.N. In silico discovery and virtual screening of multi-target inhibitors for proteins in Mycobacterium tuberculosis. Comb. Chem. High Throughput Screen., 2012, 8, 666-673. Zhang, W.; Pei, J.; Lai, L. Computational Multitarget Drug Design. J. Chem. Inf. Model., 2017, 57, 403-412. Pei, J.; Yin, N.; Ma, X.; Lai, L. Systems Biology Brings New Dimensions for Structure-Based Drug Design. J. Am. Chem. Soc., 2014, 136, 11556-11565. Nollmann, M.; Crisona, N.J.; Arimondo, P.B. Thirty years of Escherichia coli DNA gyrase: from in vivo function to single molecule mechanism. Biochimie, 2007, 89, 490-499. Bates, A.D.; Maxwell, A. Energy coupling in type ii topoisomerases: why do they hydrolyze ATP? Biochemistry, 2007, 46, 7929-7941. Champoux, J.J. DNA topoisomerases: structure, function, and mechanism. Annu. Rev. Biochem., 2001, 70, 369-413. Gellert, M.; Mizuuchi, K.; O'Dea, M.H.; Ohmori, H.; Tomizawa, J. DNA gyrase and DNA supercoiling. In: Cold Spring Harbor symposia on quantitative biology. Cold Spring Harbor Lab. Press, 1979, 43, 35-40. Kaur, P; Agarwal, S.; Datta, S. Delineating bacteriostatic and bactericidal targets in mycobacteria using IPTG inducible antisense expression. PloS One, 2009, 4(6), 5923-5938. Chopra, S.; Matsuyama, K.; Tran, T.; Malerich, J.P.; Wan, B.; Franzblau, S.G.; Lun, S.; Guo, H.; Maiga, M.C.; Bishai, W.R.; Madrid, P.B. Evaluation of gyrase B as a drug target in Mycobacterium tuberculosis. J. antimicrob. Chemother., 2012, 67(2), 415421.

de Oliveira Viana et al. [27] [28] [29]

[30] [31] [32]

[33] [34] [35] [36] [37] [38] [39] [40]

[41]

[42]

[43]

[44]

[45]

[46]

Carroll, P.; Faray-Kele, M.C.; Parish, T. Identifying vulnerable pathways in Mycobacterium tuberculosis by using a knockdown approach. Appl. Environ. Microbiol., 2011, 77, 5040-5043. Gulick, A.M. Conformational dynamics in the acyl-CoA synthetases, adenylation domains of non-ribosomal peptide synthetases, and firefly luciferase. ACS Chem. Biol., 2009, 4, 811–827. Arora, P.; Goyal, A.; Natarajan, V.T.; Rajakumara, E.; Verma, P.; Gupta, R.; Sankaranarayanan, R. Mechanistic and functional insights into fatty acid activation in Mycobacterium tuberculosis. Nat. Chem. Biol., 2009, 5, 166-173. Trivedi, O.A.; Arora, P.; Sridharan, V.; Tickoo, R.; Mohanty, D.; Gokhale, R.S. Enzymic activation and transfer of fatty acids as acyl-adenylates in mycobacteria. Nature, 2004, 428, 441-445 Goehring, N.W.; Beckwith, J. Diverse paths to midcell: assembly of the bacterial cell division machinery. Curr. Biol., 2005, 15(13), 514-526. Leung, A.K.W.; White, E.L.; Ross, L.J.; Reynolds, R.C.; DeVito, J.A.; Borhani, D.W. Structure of Mycobacterium tuberculosis FtsZ Reveals Unexpected, G Protein-like Conformational Switches. J. Mol. Biol., 2004, 342(3), 953-970. Thanedar, S.; Margolin, W. FtsZ Exhibits Rapid Movement and Oscillation Waves in Helix-like Patterns in Escherichia coli. Curr. Biol., 2004, 14(13), 1167-1173. Ben-Yehuda, S.; Losick, R. Asymmetric cell division in B. subtilis involves a spiral-like intermediate of the cytokinetic protein FtsZ. Cell, 2002, 109(2), 257-266. Moller-Jensen, J.; Loewe, J. Increasing complexity of the bacterial cytoskeleton. Curr. Opin. Cell. Biol., 2005, 17(1), 75-81. Errington, J.; Daniel, R.A.; Scheffers, D.J. Cytokinesis in bacteria. Microbiol. Mol. Biol. Rewiews, 2003, 67(1), 52-65. Goehring, N.W.; Beckwith, J. Diverse paths to midcell: assembly of the bacterial cell division machinery. Curr. Biol., 2005, 15(13), 514-526. Vollmer, W. The prokaryotic cytoskeleton: a putative target for inhibitors and antibiotics? Appl. Microbiol. Biotechnol., 2006, 73(1), 37-47. Huang, Q.; Tonge, P.J.; Slayden, R.A.; Kirikae, T.; Ojima, I. FtsZ: a novel target for tuberculosis drug discovery. Curr. Top. Med. Chem., 2007, 7(5), 527-543. Slayden, R.A.; Knudson, D.L.; Belisle, J.T. Identification of cell cycle regulators in Mycobacterium tuberculosis by inhibition of septum formation and global transcriptional analysis. Microbiology, 2006, 152(6), 1789-1797. Respicio, L.; Nair, P.A.; Huang, Q.; Burcu, A.B.; Tracz, S.; Truglio, J.J.; Kisker, C.; Raleigh, D.P.; Ojima, I.; Knudson, D.L.; Tonge, P. J.; Slayden, R. A. Characterizing septum inhibition in Mycobacterium tuberculosis for novel drug discovery. Tuberculosis, 2008, 88, 420-429. Foo, C.S.Y.; Lechartier, B.; Kolly, G.S.; Röttger, S.B.; Neres, J.; Rybniker, J.; Lupien, A.; Sala, C.; Piton, J.; Cole, S.T. Characterization of DprE1-mediated benzothiazinone resistance in Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2016, 60(11), 6451-6459. Makarov, V.; Manina, G.; Mikusova, K.; Möllmann, Y.; Ryabova, O.; Saint-joanis, B.; Dhar, N.; Pasca, M.R.; Bobovska, A.; Dianiskova, P.; Kordulakova, J.; Sala, C.; Fullam, E.; Schneider, P.; Mckinney, J.D.; Brodin, P.; Christophe, T.; Waddell, S.; Butcher, P.; Albrethsen, J.; Rosenkrands, I.; Brosch, R.; Nandi, V.; Bharath, S.; Gaonkar, S.; Shandil, R.K.; Balasubramanian, V.; Balganesh, T.; Tyagi, S.; Grosset, J.; Riccardi, G.; Cole, S.T. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science, 2009, 324(5928), 801-804. Mikusova, K.; Huang, H.; Yagi, T.; Holsters, M.; Vereecke, D.; Haeze, W.D.; Scherman, M.S.; Brennan, P.J.; Mcneil, M.R.; Crick, D.C. Decaprenylphosphoryl arabinofuranose, the donor of the Darabinofuranosyl residues of Mycobacterial arabinan, is formed via a two-step epimerization of decaprenylphosphoryl ribose. J. bacterial., 2005, 187(23), 8020-8025. Batt, S.M.; Jabeen, T.; Bhowruth, V.; Quill, L.; Lund, P.A.; Eggeling, L.; Alderwick, L.J.; Fütterer, K.; Besra, G.S. Structural basis of inhibition of Mycobacterium tuberculosis DprE1 by benzothiazinone inhibitors. Proceed. Nat. Acad. Sci, 2012, 109(28), 11354-11359. Gao, C.; Ye, T.H.; Wang, N.Y.; Zeng, X.X.; Zhang, L.D.; Xiong, Y.; You, X.Y.; Xia, Y.; Peng, C.T.; Zuo, W.Q.; Wei, Y.; Yu, L.T. Synthesis and structure–activity relationships evaluation of ben-

Multi-Target Antitubercular Drugs

[47]

[48]

[49] [50]

[51]

[52] [53]

[54]

[55]

[56]

[57] [58] [59]

[60]

[61]

zothiazinone derivatives as potential anti-tubercular agents. Bioorg. Med. Chem. Lett., 2013, 23(17), 4919-4922. Neres, J.; Pojer, F.; Molteni, E.; Chiarelli, L.R.; Dhar, N.; Boyröttger, S.; Buroni, S.; Fullam, E.; Degiacomi, G.; Lucarelli, A.P.; Read, R.J.; Zanoni, G.; Edmondson, D.E.; Rossi, E.; Pasca, M.R.; Mckinney, J.D.; Dyson, P.J.; Riccardi, G.; Mattevi, A.; Cole, S.T.; Binda, C. Structural Basis for Benzothiazinone-Mediated Killing of Mycobacterium tuberculosis. Sci. Transl. Med., 2012, 4(150), 121150. Trefzer, C.; Gonzalez, M.R.; Hinner, M.J.; Schneider, P.; Makarov, V.; Cole, S.T.; Johnsson, K. Benzothiazinones: Prodrugs That Covalently Modify the Decaprenylphosphoryl-β-D-ribose 2′epimerase DprE1 of Mycobacterium tuberculosis. J. Am. Chem. Soc., 2010, 132, 13663–13665. Trefzer, C. DprE1 as a Drug Target from Mycobacterium Tuberculosis. 2012. Ribeiro, A.L.J.L.; Degiacomi, G.; Ewann, F.; Buroni, S.; Incandela, M.L.; Chiarelli, L.R.; Mori, G.; Kim, J.; Dominguez, M.C.; Park, Y.S.; Han, S.J.; Brodin, P.; Valentini, G.; Rizzi, M.; Riccardi, G.; Pasca, M.R. Analogous mechanisms of resistance to benzothiazinones and dinitrobenzamides in Mycobacterium smegmatis. PloS one, 2011, 6(11), e26675. Makarov, V.; Lechartier, B.; Zhang, M.; Neres, J.; Sar, A.M.V.; Raadsen, S.A.; Hartkoorn, R.C.; Ryabova, O.B.; Vocat, A.; Decosterd, L.A.; Widmer, N.; Buclin, T.; Bitter, W.; Andries, K.; Pojer, F.; Dyson, P.J.; Cole, S.T. Towards a new combination therapy for tuberculosis with next generation benzothiazinones. EMBO Mol. Med., 2014, e201303575. Vaganay, S.; Tanner, M.E.; van Heijenoort, J.; Blanot, D. Study of the reaction mechanism of the d-glutamic acid-adding enzyme from Escherichia coli. Microb. Drug Resist., 1996, 2, 51-54. Gordon, E.; Flouret, B.; Chantalat, L.; van Heijenoort, J.; MenginLecreulx, D. Dideberg, O. Crystal structure of UDP-Nacetylmuramoyl-L-alanyl-D-glutamate: meso-diaminopimelate ligase from Escherichia coli. J. Biol. Chem., 2001, 276, 1099911006. Bouhss, A.; Mengin-Lecreulx, D.; Blanot, D.; van Heijenoort, J.; Parquet, C. Invariant amino acids in the Mur peptide synthetases of bacterial peptidoglycan synthesis and their modification by sitedirected mutagenesis in the UDP-MurNAc:L-alanine ligase from Escherichia coli. Biochemistry, 1997, 36, 11556–11563. Eveland, S.S.; Pompliano, D.L.; Anderson, M.S. Conditionally lethal Escherichia coli murein mutants contain point defects that map to regions conserved among murein and folyl poly-gammaglutamate ligases: identification of a ligase superfamily. Biochemistry, 1997, 36, 6223-6229. Walsh, A.W.; Falk, P.J.; Thanassi, J.; Discotto, L.; Pucci, M.J.; Ho, H.T. Comparison of the D-glutamateadding enzymes from selected gram-positive and gramnegative bacteria. J Bacteriol, 1999, 181, 5395-5401. El Zoeiby, A.; Sanschagrin, F.; Levesque, R.C. Structure and function of the Mur enzymes: development of novel inhibitors. Mol Microbiol., 2003, 47, 1-12. Smith, C.A. Structure, function and dynamics in the mur family of bacterial cell wall ligases. J. Mol. Biol., 2006, 362, 640-655. Munshi, T.; Gupta, A.; Evangelopoulos, D.; Guzman, J. D.; Gibbons, S.; Keep, N. H.; Bhakta, S. Characterisation of ATPdependent Mur ligases involved in the biogenesis of cell wall peptidoglycan in Mycobacterium tuberculosis. PLoS One, 2013, 8(3), e60143. Cole, S.T.; Brosch, R.; Parkhill, J.; Garnier, T.; Churcher, C.; Harris, D.; Gordon, S.V.; Eiglmeier, K.; Gas, S.; Barry, C.E.; Tekaia, F.; Badcock, K.; Basham, D.; Brown, D.; Chillingworth, T.; Connor, R.; Davies, R.; Devlin, K.; Feltwell, T.; Gentles, S.; Hamlin, N.; Holroyd, S.; Hornsby, T.; Jagels, K.; Krogh, A.; McLean, J.; Moule, S.; Murphy, L.; Oliver, K.; Osborne, J.; Quail, M.A,. Rajandream, M.A.; Rogers, J.; Rutter, S.; Seeger, K.; Skelton, J.; Squares, R.; Squares, S.; Sulston, J.E.; Taylor, K.; Whitehead, S.; Barrell, B.G. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature, 1998, 393, 537544. Deva, T.; Baker, E.N.; Squire, C.J.; Smith, C.A. Structure of Escherichia coli UDP-N-acetylmuramoyl:Lalanine ligase (MurC). Acta Crystallogr. D: Biol. Crystallogr., 2006, 62, 1466-1474.

Current Topics in Medicinal Chemistry, 2018, Vol. 18, No. 00 [62] [63]

[64]

[65] [66] [67]

[68]

[69]

[70]

[71]

[72] [73]

[74]

[75]

[76]

[77] [78]

[79] [80] [81] [82]

7

Anishetty, S.; Pulimi, M.; Pennathur, G. Potential drug targets in Mycobacterium tuberculosis through metabolic pathway analysis. Comput. Biol. Chem., 2005, 29, 368-378. Walsh, A.W.; Falk, P.J.; Thanassi, J.; Discotto, L.; Pucci, M.J.; Ho, H.T. Comparison of the D-glutamateadding enzymes from selected gram-positive and gramnegative bacteria. J. Bacteriol., 1999, 181, 5395–5401. Consaul, S.A.; Wright, L.F.; Mahapatra, S.; Crick, D.C.; Pavelka, M.S.; An unusual mutation results in the replacement of diaminopimelate with lanthionine in the peptidoglycan of a mutant strain of Mycobacterium smegmatis. J. Bacteriol., 2005, 187, 1612-1620. Smith, C.A. Structure, function and dynamics in the mur family of bacterial cell wall ligases. J. Mol. Biol., 2006, 362, 640-655. Silhavy, T.J.; Kahne, D.; Walker, S. The bacterial cell envelope. Cold Spring Harb. Perspect. Biol., 2010, 2, e414. Grzegorzewicz, A.E.; Pham, H.; Gundi, V.A.; Scherman, M.S.; North, E.J.; Hess, T.; Jones, V.; Gruppo, V.; Born, S.E.; Korduláková, J.; Chavadi, S.S.; Morisseau, C.; Lenaerts, A.J.; Lee, R.E.; McNeil, M.R.; Jackson, M. Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane. Nat. Chem. Biol., 2012, 8, 334-341. Hoffmann, C.; Leis, A.; Niederweis, M.; Plitzko, J.M.; Engelhardt, H. Disclosure of the mycobacterial outer membrane: cryo-electron tomography and vitreous sections reveal the lipid bilayer structure. Proc. Natl. Acad. Sci., 2008, 105, 3963-3967. Zuber, B.; Chami, M.; Houssin, C.; Dubochet, J.; Griffiths, G.; Daffé, M. Direct visualization of the outer membrane of mycobacteria and corynebacterial in their native state. J. Bacteriol., 2008, 190, 5672-5680. Kolappan, S.; Zwahlen, J.; Zhou, R.; Truglio, J.J; Tonge, P.J; Kisker, C. Lysine 190 is the catalytic base in MenF, the menaquinone-specific isochorismate synthase from Escherichia coli: implications for an enzyme family. Biochemistry., 2007, 46, 946-953. Dawson, A.; Chen, M.; Fyfe, P.K.; Guo, Z.; Hunter, W.N. Structure and reactivity of Bacillus subtilis MenD catalyzing the first committed step in menaquinone biosynthesis. J. Mol. Biol., 2010, 401, 253-264. Paudel, A.; Hamamoto, H.; Panthee, S.; Sekimizu, K. Menaquinone as a potential target of antibacterial agents. Drug Disc. Therap., 2016, 10(3), 123-128. Lu, X.; Zhang, H.; Tonge, P.J.; Tan, D.S. Mechanism-based inhibitors of MenE, an acyl-CoA synthetase involved in bacterial menaquinone biosynthesis. Bioorg. Med. Chem. Lett., 2008, 18, 5963-5966. Zhang, H.; Tonge, P.J. The mechanism of the reactions catalyzed by 1,4-dihydroxynaphthoyl-CoA synthase (MenB) and 2- ketocyclohexanecarboxyl-CoA hydrolase (BadI). Amer. Chem. Soc., 2007, 234, 19-23. Li, X.; Zhang, H.; Tonge, P. J. Inhibition of 1,4dihydroxynaphthoyl-CoA synthase (MenB), an enzyme drug target bacterial menaquinone biosynthesis pathway. 36th ACS National Meeting, Philadelphia, 2008; pp. 17-21. Xu, H.; Graham, M.; Karelis, J.; Walker, S.G.; Peter, J.; Tonge, P.J. Mechanistic studies of MenD, 2-succinyl-5-enoylpyruvyl-6hydroxy-3-cyclohexene-1-carboxylic acid synthase from Staphylococcus aureus. 237th ACS National Meeting, 2009; pp. 22-26. von Ballmoos, C.; Cook, G.M.; Dimroth, P. Unique rotary ATP synthase and its biological diversity. Annu. Rev. Biophys., 2008, 37, 43-64. de Jonge, M.R.; Koymans, L.H.; Guillemont, J.E.; Koul, A.; Andries, K. A computational model of the inhibition of Mycobacterium tuberculosis ATPase by a new drug candidate R207910. Proteins, 2007, 67, 971-980. Lake, B.G. Coumarin metabolism, toxicity and carcinogenicity: relevance for human risk assessment. Food and Chemical Toxicology, 1999, 37(4), 423-453. Lacy, A.; O’Kennedy, R. Studies on coumarins and coumarinrelated compounds to determine their therapeutic role in the treatment of cancer. Curr. Pharmac.Design, 2004, 10(30), 3797-3811. Staudenbauer, W.L.; Orr, E. DNA gyrase: affinity chromatography on novobiocinsepharose and catalytic properties. Nucleic Acids Res., 1981, 9, 3589-3603. Kawate, T.; Iwase, N.; Shimizu, M.; Stanley, S. A.; Wellington, S.; Kazyanskaya, E.; Hung, D.T. Synthesis and structure–activity relationships of phenyl-substituted coumarins with anti-tubercular ac-

8 Current Topics in Medicinal Chemistry, 2018, Vol. 18, No. 00

[83]

[84] [85]

[86] [87]

[88]

[89]

tivity that target FadD32. Bioorg.med. chem. lett., 2013, 23(22), 6052-6059. Stanley, S.A.; Kawate, T.; Iwasea, N.; Shimizua, M.; Clatworthya, A.E.; Kazyanskayaa, E.; Sacchettinid, J.C.; Ioergere, T.R.; Siddiqif, N.A.; Minamif, S.; Aquadroa, J.A.; Granta, S.S.; Rubinf, E.J.; Hunga, D.T. Diarylcoumarins inhibit mycolic acid biosynthesis and kill Mycobacterium tuberculosis by targeting FadD32. Proceed. Nat. Acad. Sci., 2013, 110(28), 11565-11570. Sridevi, D.; Sudhakar, K.U.; Ananthathatmula, R.; Nankar, R.P.; Doble, M. Mutation at G103 of MtbFtsZ Altered their Sensitivity to Coumarins. Front. microb., 2017, 8(578), e.12 Shaikh, M.H.; Subhedar, D.D.; Shingate, B.B.; Khan, F.A.K.; Sangshetti, J.N.; Khedkar, V.M.; Navale, K.; Sarkar, D.; Navale, G.R.; Shinde, S.S. Synthesis, biological evaluation and molecular docking of novel coumarin incorporated triazoles as antitubercular, antioxidant and antimicrobial agents. Med. Chem. Research, 2016, 25(4), 790-804. Wigley, D.B. Structure and mechanism of DNA gyrase. Nucleic Acids Molec. Biol., 1995, 165-176. Ji, B.; Lounis, N.; Maslo, C.; Truffot-Pernot, C.; Bonnafous, P.; Grosset, J. In vitro and in vivo activities of moxifloxacin and clinafloxacin against Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 1998, 42, 2066–2069. Tomioka, H.; Sato, K.; Akaki, T.; Kajitani, H.; Kawahara, S.; Sakatani, M. Comparative in vitro antimicrobial activities of the newly synthesized quinolone HSR-903, sitafloxacin (DU-6859a), gatifloxacin (AM-1155), and levofloxacin against Mycobacterium tuberculosis and Mycobacterium avium complex. Antimicrob. Agents Chemother., 1999, 43, 3001–3004. Minovski, N.; Perdih, A.; Solmajer, T. Combinatorially-generated library of 6-fluoroquinolone analogs as potential novel antitubercular agents: a chemometric and molecular modeling assessment. J. mol. Model., 2012, 18(5), 1735-1753.

de Oliveira Viana et al. [90]

[91]

[92] [93]

[94]

Guzman, J.D.; Wube, A.; Evangelopoulos, D.; Gupta, A.; Hüfner, A.; Basavannacharya, C.; Rahman, M.M.; Thomaschitz, C.; Bauer, R.; McHugh, T.D.; Nobeli, I.; Prieto, J.M.; Gibbons, S.; Bucar, F.; Bhakta, S. Interaction of N-methyl-2-alkenyl-4-quinolones with ATP-dependent MurE ligase of Mycobacterium tuberculosis: antibacterial activity, molecular docking and inhibition kinetics. J. antimicrob. Chemother., 2011, 66(8), 1766-1772. Guzman, J.D.; Pesnot, T.; Barrera, D.A.; Davies, H.M.; McMahon, E.; Evangelopoulos, D.; Mortazavi, P.N.; Munshi, T.; Maitra, A.; Lamming, E.D.; Angell, R.; Gershater, M.C.; Redmond, J.M.; Needham, D.; Ward, J.M.; Cuca, L.E.; Hailes, H.C.; Bhakta, S. Tetrahydroisoquinolines affect the whole-cell phenotype of Mycobacterium tuberculosis by inhibiting the ATP-dependent MurE ligase. J. Antimic. Chemother., 2015, 70(6), 1691-1703. New TB drugs. https://www.newtbdrugs.org/pipeline/compound/sq109 (Accessed August 21, 2017). Tahlan, K.; Wilson, R.; Kastrinsky, D.B.; Arora, K.; Nair, V.; Fischer, E.; Barnes, W.; Walker, J.R.; Alland, D.; Barry, C.E.; Boshoff, H. SQ109 Targets MmpL3, a Membrane Transporter of Trehalose Monomycolate Involved in Mycolic Acid Donation to the Cell Wall Core of Mycobacterium tuberculosis. Antimicrob. Agents Chemother., 2012, 1797–1809. Li, K.; Schurig-Briccio, L.A.; Feng, X.; Upadhyay, A.; Pujari, V.; Lechartier, B.; Fontes, F.L.; Yang,, H.; Rao, G.; Zhu, W.; Gulati, A.; No, J.H.; Cintra, G.; Bogue, S.; Liu, Y.L.; Molohon, K.; Orlean, P.; Mitchell, D.A.; Junior, L.F.; Ren, F.; Sun, H.; Jiang, T.; Li, Y.; Guo, R.T.; Cole, S.T.; Gennis, R.B.; Crick, D.C.; Oldfield, E. Multitarget Drug Discovery for Tuberculosis and Other Infectious Diseases. J. Med. Chem., 2014, 57, 3126-3139.

DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the author. The Editorial Department reserves the right to make minor modifications for further improvement of the manuscript.