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Infectious Disorders - Drug Targets

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ISSN (Print): 1871-5265
ISSN (Online): 2212-3989

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Recent Discoveries of Nitrogen-Containing Heterocyclic Compounds as InhA Inhibitors against Mycobacterium tuberculosis: An Overview

Author(s): Pratibha D. Gupta, Kalpana N. Tilekar, Neha M. Upadhyay and Ramaa C.S*

Volume 22, Issue 8, 2022

Published on: 18 August, 2022

Article ID: e200422203820 Pages: 11

DOI: 10.2174/1871526522666220420092618

Price: $65

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Abstract

It is a formidable challenge to treat tuberculosis as there are increasing cases of multidrugresistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) cases. Moreover, the emergence of totally drug-resistant tuberculosis (TDR-TB) makes it vital and imperative to develop a new generation of anti-tubercular drugs to have control over resistance. The nitrogencontaining heterocyclic class of compounds is being studied extensively to ascertain their anti-TB potentials. Nitrogen-containing compounds have a broad range of targets; wherein, InhA is the most important one. Hence, the primary focus of this review is to summarize the recent developments in the discovery of nitrogen-containing heterocyclic compounds as InhA inhibitors to combat tuberculosis.

Keywords: Tuberculosis, Anti-tuberculosis agents, InhA inhibitors, Isoniazid, Triclosan, GEQ Heterocycle.

Graphical Abstract

[1]
Global tuberculosis report 2020. Geneva: World Health Organization;. 2020. Licence: CC BY-NC-SA 3.0 IGO. 2020. Available from: https://www.who.int/publications-detail-redirect/9789240013131 (accessed 2021 -10 -27).
[2]
Martínez-Hoyos M, Perez-Herran E, Gulten G, et al. Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor. EBioMedicine 2016; 8: 291-301.
[http://dx.doi.org/10.1016/j.ebiom.2016.05.006] [PMID: 27428438]
[3]
Seung KJ, Keshavjee S, Rich ML. Multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. Cold Spring Harb Perspect Med 2015; 5(9): a017863.
[http://dx.doi.org/10.1101/cshperspect.a017863] [PMID: 25918181]
[4]
Lange C, Abubakar I, Alffenaar J-WC, et al. TBNET. Management of patients with multidrug-resistant/extensively drug-resistant tuberculosis in Europe: A TBNET consensus statement. Eur Respir J 2014; 44(1): 23-63.
[http://dx.doi.org/10.1183/09031936.00188313] [PMID: 24659544]
[5]
Laniado-Laborín R. Clinical challenges in the era of multiple and extensively drug-resistant tuberculosis. Rev Panam Salud Publica 2017; 41: e167.
[http://dx.doi.org/10.26633/RPSP.2017.167] [PMID: 31384279]
[6]
Migliori GB, Sotgiu G, D’Arcy Richardson M, et al. TBNET. MDR-TB and XDR-TB: Drug resistance and treatment outcomes. Eur Respir J 2009; 34(3): 778-9.
[http://dx.doi.org/10.1183/09031936.00059409] [PMID: 19720816]
[7]
Singh R, Dwivedi SP, Gaharwar US, Meena R, Rajamani P, Prasad T. Recent updates on drug resistance in Mycobacterium tuberculosis. J Appl Microbiol 2020; 128(6): 1547-67.
[http://dx.doi.org/10.1111/jam.14478] [PMID: 31595643]
[8]
Yao C, Guo H, Li Q, et al. Prevalence of extensively drug-resistant tuberculosis in a Chinese multidrug-resistant TB cohort after redefinition. Antimicrob Resist Infect Control 2021; 10(1): 126.
[http://dx.doi.org/10.1186/s13756-021-00995-8] [PMID: 34446095]
[9]
Choudhary B, Purohit G, Choudhary CR. A study of proportion of comorbidities in multidrug resistant tuberculosis patients in a tertiary care centre of western rajasthan. IOSR-JDMS 2021; 20(4): 01-6.
[http://dx.doi.org/10.9790/0853-2004030106]
[10]
Armstrong T, Lamont M, Lanne A, Alderwick LJ, Thomas NR. Inhibition of Mycobacterium tuberculosis InhA: Design, synthesis and evaluation of new di-triclosan derivatives. Bioorg Med Chem 2020; 28(22): 115744.
[http://dx.doi.org/10.1016/j.bmc.2020.115744] [PMID: 33007556]
[11]
Lan Z, Ahmad N, Baghaei P, et al. Collaborative group for the meta-analysis of individual patient data in MDR-TB treatment 2017. Drug-associated adverse events in the treatment of multidrug-resistant tuberculosis: An individual patient data meta-analysis. Lancet Respir Med 2020; 8(4): 383-94.
[http://dx.doi.org/10.1016/S2213-2600(20)30047-3] [PMID: 32192585]
[12]
Aftab A, Afzal S, Qamar Z, Idrees M. Early detection of MDR Mycobacterium tuberculosis mutations in Pakistan. Sci Rep 2021; 11(1): 16736.
[http://dx.doi.org/10.1038/s41598-021-96116-x] [PMID: 34408186]
[13]
Chetty S, Armstrong T, Sharma Kharkwal S, et al. New InhA inhibitors based on expanded triclosan and Di-triclosan analogues to develop a new treatment for tuberculosis. Pharmaceuticals (Basel) 2021; 14(4): 361.
[http://dx.doi.org/10.3390/ph14040361] [PMID: 33919737]
[14]
Ananthan S, Faaleolea ER, Goldman RC, et al. High-throughput screening for inhibitors of Mycobacterium tuberculosis H37Rv. Tuberculosis (Edinb) 2009; 89(5): 334-53.
[http://dx.doi.org/10.1016/j.tube.2009.05.008] [PMID: 19758845]
[15]
Ramesh D, Joji A, Vijayakumar BG, Sethumadhavan A, Mani M, Kannan T. Indole chalcones: Design, synthesis, in vitro and in silico evaluation against Mycobacterium tuberculosis. Eur J Med Chem 2020; 198: 112358.
[http://dx.doi.org/10.1016/j.ejmech.2020.112358] [PMID: 32361610]
[16]
Degiacomi G, Belardinelli JM, Pasca MR, De Rossi E, Riccardi G, Chiarelli LR. Promiscuous targets for antitubercular drug discovery: The paradigm of DprE1 and MmpL3. Appl Sci (Basel) 2020; 10(2): 623.
[http://dx.doi.org/10.3390/app10020623]
[17]
Debnath J, Siricilla S, Wan B, et al. Discovery of selective menaquinone biosynthesis inhibitors against Mycobacterium tuberculosis. J Med Chem 2012; 55(8): 3739-55.
[http://dx.doi.org/10.1021/jm201608g] [PMID: 22449052]
[18]
Cleghorn LAT, Ray PC, Odingo J, et al. Identification of morpholino thiophenes as novel Mycobacterium tuberculosis inhibitors, targeting QcrB. J Med Chem 2018; 61(15): 6592-608.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00172] [PMID: 29944372]
[19]
Zhang W, Lun S, Wang S-H, et al. Identification of novel coumestan derivatives as polyketide synthase 13 inhibitors against Mycobacterium tuberculosis. J Med Chem 2018; 61(3): 791-803.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01319] [PMID: 29328655]
[20]
Pflégr V, Horváth L, Stolaříková J, et al. Design and synthesis of 2-(2-isonicotinoylhydrazineylidene)propanamides as InhA inhibitors with high antitubercular activity. Eur J Med Chem 2021; 223: 113668.
[http://dx.doi.org/10.1016/j.ejmech.2021.113668] [PMID: 34198149]
[21]
Holas O, Ondrejcek P, Dolezal M. Mycobacterium tuberculosis enoyl-acyl carrier protein reductase inhibitors as potential antituberculotics: Development in the past decade. J Enzyme Inhib Med Chem 2015; 30(4): 629-48.
[http://dx.doi.org/10.3109/14756366.2014.959512] [PMID: 25383419]
[22]
Vannelli TA, Dykman A, Ortiz de Montellano PR. The antituberculosis drug ethionamide is activated by a flavoprotein monooxygenase. J Biol Chem 2002; 277(15): 12824-9.
[http://dx.doi.org/10.1074/jbc.M110751200] [PMID: 11823459]
[23]
Halloum I, Viljoen A, Khanna V, et al. Resistance to thiacetazone derivatives active against Mycobacterium abscessus involves mutations in the MMPL5 transcriptional repressor MAB_4384. Antimicrob Agents Chemother 2017; 61(4): e02509-16.
[http://dx.doi.org/10.1128/AAC.02509-16] [PMID: 28096157]
[24]
Schaaf HS, Victor TC, Venter A, et al. Ethionamide cross- and co-resistance in children with isoniazid-resistant tuberculosis. Int J Tuberc Lung Dis 2009; 13(11): 1355-9.
[PMID: 19861006]
[25]
Silva MSN, Senna SG, Ribeiro MO, et al. Mutations in katG, inhA, and ahpC genes of Brazilian isoniazid-resistant isolates of Mycobacterium tuberculosis. J Clin Microbiol 2003; 41(9): 4471-4.
[http://dx.doi.org/10.1128/JCM.41.9.4471-4474.2003] [PMID: 12958298]
[26]
Duan X, Xiang X, Xie J. Crucial components of Mycobacterium type II fatty acid biosynthesis (Fas-II) and their inhibitors. FEMS Microbiol Lett 2014; 360(2): 87-99.
[http://dx.doi.org/10.1111/1574-6968.12597] [PMID: 25227413]
[27]
Marrakchi H, Lanéelle M-A, Daffé M. Mycolic acids: Structures, biosynthesis, and beyond. Chem Biol 2014; 21(1): 67-85.
[http://dx.doi.org/10.1016/j.chembiol.2013.11.011] [PMID: 24374164]
[28]
Pitaloka DAE, Ramadhan DSF. Arfan, Chaidir L, Fakih TM. Docking-based virtual screening and molecular dynamics simulations of quercetin analogs as enoyl-acyl carrier protein reductase (InhA) inhibitors of Mycobacterium tuberculosis. Sci Pharm 2021; 89(2): 20.
[http://dx.doi.org/10.3390/scipharm89020020]
[29]
Luckner SR, Liu N, Am Ende CW, Tonge PJ, Kisker C. A slow, tight binding inhibitor of InhA, the enoyl-acyl carrier protein reductase from Mycobacterium tuberculosis. J Biol Chem 2010; 285(19): 14330-7.
[http://dx.doi.org/10.1074/jbc.M109.090373] [PMID: 20200152]
[30]
Rozwarski DA, Vilchèze C, Sugantino M, Bittman R, Sacchettini JC. Crystal structure of the Mycobacterium tuberculosis enoyl-ACP reductase, InhA, in complex with NAD+ and a C16 fatty acyl substrate. J Biol Chem 1999; 274(22): 15582-9.
[http://dx.doi.org/10.1074/jbc.274.22.15582] [PMID: 10336454]
[31]
Guardia A, Gulten G, Fernandez R, et al. N-Benzyl-4-((heteroaryl)methyl)benzamides: A new class of direct NADH-Dependent 2-trans enoyl-acyl carrier protein reductase (inha) inhibitors with antitubercular activity. ChemMedChem 2016; 11(7): 687-701.
[http://dx.doi.org/10.1002/cmdc.201600020] [PMID: 26934341]
[32]
Rivière E, Whitfield MG, Nelen J, Heupink TH, Van Rie A. Identifying isoniazid resistance markers to guide inclusion of high-dose isoniazid in tuberculosis treatment regimens. Clin Microbiol Infect 2020; 26(10): 1332-7.
[http://dx.doi.org/10.1016/j.cmi.2020.07.004] [PMID: 32653663]
[33]
Vora D, Upadhyay N, Tilekar K, Jain V, Ramaa CS. Development of 1,2,4-triazole-5-thione derivatives as potential inhibitors of enoyl acyl carrier protein reductase (InhA) in tuberculosis. Iran J Pharm Res 2019; 18(4): 1742-58.
[http://dx.doi.org/10.22037/ijpr.2019.112039.13495] [PMID: 32184843]
[34]
Kerru N, Gummidi L, Maddila S, Gangu KK, Jonnalagadda SB. A review on recent advances in nitrogen-containing molecules and their biological applications. Molecules 2020; 25(8): 1909.
[http://dx.doi.org/10.3390/molecules25081909] [PMID: 32326131]
[35]
Heravi MM, Zadsirjan V. Prescribed drugs containing nitrogen heterocycles: An overview. RSC Advances 2020; 10(72): 44247-311.
[http://dx.doi.org/10.1039/D0RA09198G]
[36]
Szatylowicz H, Stasyuk OA, Krygowski TM. Substituent effects in heterocyclic systems Advances in heterocyclic chemistry. Elsevier 2015; Vol. 116: pp. 137-92.
[http://dx.doi.org/10.1016/bs.aihch.2015.05.002]
[37]
Hamid H, Inh A. Inhibitors as potential antitubercular agents. Orient J Chem 2016; 32(1): 59-75.
[http://dx.doi.org/10.13005/ojc/320106]
[38]
Lone MY, Manhas A, Athar M, Jha PC. Identification of InhA inhibitors: A combination of virtual screening, molecular dynamics simulations and quantum chemical studies. J Biomol Struct Dyn 2018; 36(11): 2951-65.
[http://dx.doi.org/10.1080/07391102.2017.1372313] [PMID: 28849732]
[39]
Ekins S, Madrid PB, Sarker M, et al. Combining metabolite-based pharmacophores with bayesian machine learning models for Mycobacterium tuberculosis drug discovery. PLoS One 2015; 10(10): e0141076.
[http://dx.doi.org/10.1371/journal.pone.0141076] [PMID: 26517557]
[40]
Doğan ŞD, Gündüz MG, Doğan H, Krishna VS, Lherbet C, Sriram D. Design and synthesis of thiourea-based derivatives as Mycobacterium tuberculosis growth and enoyl acyl carrier protein reductase (InhA) inhibitors. Eur J Med Chem 2020; 199: 112402.
[http://dx.doi.org/10.1016/j.ejmech.2020.112402] [PMID: 32417538]
[41]
Ribeiro RCB, de Marins DB, Di Leo I, et al. Anti-tubercular profile of new selenium-menadione conjugates against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain and multidrug-resistant clinical isolates. Eur J Med Chem 2021; 209: 112859.
[http://dx.doi.org/10.1016/j.ejmech.2020.112859] [PMID: 33010635]
[42]
Punkvang A, Saparpakorn P, Hannongbua S, Wolschann P, Pungpo P. Elucidating drug-enzyme interactions and their structural basis for improving the affinity and potency of isoniazid and its derivatives based on computer modeling approaches. Molecules 2010; 15(4): 2791-813.
[http://dx.doi.org/10.3390/molecules15042791] [PMID: 20428080]
[43]
He X, Alian A, Stroud R, Ortiz de Montellano PR. Pyrrolidine carboxamides as a novel class of inhibitors of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis. J Med Chem 2006; 49(21): 6308-23.
[http://dx.doi.org/10.1021/jm060715y] [PMID: 17034137]
[44]
Pajk S, Živec M, Šink R, et al. New direct inhibitors of InhA with antimycobacterial activity based on a tetrahydropyran scaffold. Eur J Med Chem 2016; 112: 252-7.
[http://dx.doi.org/10.1016/j.ejmech.2016.02.008] [PMID: 26900657]
[45]
Pedgaonkar GS, Sridevi JP, Jeankumar VU, et al. Development of 2-(4-oxoquinazolin-3(4H)-yl)acetamide derivatives as novel enoyl-acyl carrier protein reductase (InhA) inhibitors for the treatment of tuberculosis. Eur J Med Chem 2014; 86: 613-27.
[http://dx.doi.org/10.1016/j.ejmech.2014.09.028] [PMID: 25218910]
[46]
Joshi SD, Kumar SRP, Patil S, et al. Chemical synthesis, molecular modeling and pharmacophore mapping of new pyrrole derivatives as inhibitors of InhA enzyme and Mycobacterium tuberculosis growth. Med Chem Res 2019; 28(11): 1838-63.
[http://dx.doi.org/10.1007/s00044-019-02418-1]
[47]
Zhang L, Wu D, Liang J, Wang L, Zhou Y. Triclosan transformation and impact on an elemental sulfur-driven sulfidogenic process. Chem Eng J 2021; 421: 129634.
[http://dx.doi.org/10.1016/j.cej.2021.129634]
[48]
Vosátka R, Krátký M, Vinšová J. Triclosan and its derivatives as antimycobacterial active agents. Eur J Pharm Sci 2018; 114: 318-31.
[http://dx.doi.org/10.1016/j.ejps.2017.12.013] [PMID: 29277667]
[49]
Heath RJ, Rubin JR, Holland DR, Zhang E, Snow ME, Rock CO. Mechanism of triclosan inhibition of bacterial fatty acid synthesis. J Biol Chem 1999; 274(16): 11110-4.
[http://dx.doi.org/10.1074/jbc.274.16.11110] [PMID: 10196195]
[50]
Schroeder EK, de Souza N, Santos DS, Blanchard JS, Basso LA. Drugs that inhibit mycolic acid biosynthesis in Mycobacterium tuberculosis. Curr Pharm Biotechnol 2002; 3(3): 197-225.
[http://dx.doi.org/10.2174/1389201023378328] [PMID: 12164478]
[51]
Kumar UC, Bvs SK, Mahmood S, et al. Discovery of novel InhA reductase inhibitors: Application of pharmacophore- and shape-based screening approach. Future Med Chem 2013; 5(3): 249-59.
[http://dx.doi.org/10.4155/fmc.12.211] [PMID: 23464516]
[52]
Rodriguez F, Saffon N, Sammartino JC, Degiacomi G, Pasca MR, Lherbet C. First triclosan-based macrocyclic inhibitors of InhA enzyme. Bioorg Chem 2020; 95: 103498.
[http://dx.doi.org/10.1016/j.bioorg.2019.103498] [PMID: 31855823]
[53]
Menendez C, Gau S, Lherbet C, et al. Synthesis and biological activities of triazole derivatives as inhibitors of InhA and antituberculosis agents. Eur J Med Chem 2011; 46(11): 5524-31.
[http://dx.doi.org/10.1016/j.ejmech.2011.09.013] [PMID: 21944473]
[54]
Stec J, Vilchèze C, Lun S, et al. Biological evaluation of potent triclosan-derived inhibitors of the enoyl-acyl carrier protein reductase InhA in drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis. ChemMedChem 2014; 9(11): 2528-37.
[http://dx.doi.org/10.1002/cmdc.201402255] [PMID: 25165007]
[55]
Ibrahim TS, Taher ES, Samir E, et al. In vitro antimycobacterial activity and physicochemical characterization of diaryl ether triclosan analogues as potential InhA reductase inhibitors. Molecules 2020; 25(14): 3125.
[http://dx.doi.org/10.3390/molecules25143125] [PMID: 32650556]
[56]
Kuo MR, Morbidoni HR, Alland D, et al. Targeting tuberculosis and malaria through inhibition of Enoyl reductase: Compound activity and structural data. J Biol Chem 2003; 278(23): 20851-9.
[http://dx.doi.org/10.1074/jbc.M211968200] [PMID: 12606558]
[57]
Chollet A, Mori G, Menendez C, et al. Design, synthesis and evaluation of new GEQ derivatives as inhibitors of InhA enzyme and Mycobacterium tuberculosis growth. Eur J Med Chem 2015; 101: 218-35.
[http://dx.doi.org/10.1016/j.ejmech.2015.06.035] [PMID: 26142487]
[58]
Suresh A, Srinivasarao S, Agnieszka N, et al. Design and synthesis of 9H-fluorenone based 1,2,3-triazole analogues as Mycobacterium tuberculosis InhA inhibitors. Chem Biol Drug Des 2018; 91(6): 1078-86.
[http://dx.doi.org/10.1111/cbdd.13127] [PMID: 29063733]
[59]
Matviiuk T, Madacki J, Mori G, et al. Pyrrolidinone and pyrrolidine derivatives: Evaluation as inhibitors of InhA and Mycobacterium tuberculosis. Eur J Med Chem 2016; 123: 462-75.
[http://dx.doi.org/10.1016/j.ejmech.2016.07.028] [PMID: 27490025]
[60]
Shaikh MS, Kanhed AM, Chandrasekaran B, et al. Discovery of novel N-methyl carbazole tethered rhodanine derivatives as direct inhibitors of Mycobacterium tuberculosis InhA. Bioorg Med Chem Lett 2019; 29(16): 2338-44.
[http://dx.doi.org/10.1016/j.bmcl.2019.06.015] [PMID: 31227345]
[61]
Manjunatha UHS, Rao SP, Kondreddi RR, et al. Direct inhibitors of InhA are active against Mycobacterium tuberculosis. Sci Transl Med 2015; 7(269): 269ra3.
[http://dx.doi.org/10.1126/scitranslmed.3010597] [PMID: 25568071]

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