The key players in the arsenal of combating TB; reviewing the lead InhA inhibitors

Document Type : Review Article

Authors

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Egypt

Abstract

After decades of decline, tuberculosis (TB) cases are continuously increasing worldwide, mostly in developing countries. Although it has not been regarded as fatal now, the TB situation may become worse with the appearance of multi-drug resistant strains (MDR-TB) that do not respond to the most common anti-TB medications, isoniazid and rifampicin. In certain cases, even more severe drug-resistant TB may emerge. Extensively drug-resistant (XDR-TB), is a form of multidrug-resistant TB that also exhibits resistance to other anti-TB agents. The enoyl acyl carrier protein reductase (InhA) enzyme, a crucial regulator of TB mycolic acid biosynthesis, is attracting considerable attention as a druggable molecular target for combating TB and surmounting its resistance mechanisms. The current review covers the currently available anti-TB medications, including the most recently FDA-approved therapy, highlighting their modes of action. In addition, it provides brief structure-activity relationship data and resistance mechanisms halting their efficacy, with a special focus on InhA as an emerging anti-TB target, as well as an overview of the most promising novel lead inhibitors classified according to their chemical entities.

Keywords

Main Subjects

References

  1. Velankar H. Tuberculous Otitis Media with Facial Paralysis-Case Report and Review of Literature. Otolaryngology Open Access Journal. 2018;3(2).
  2. https://www.who.int/en/news-room/fact-sheets/detail/tuberculosis, accessed in February 2023.
  3. Konstantinos A. Diagnostic tests: Testing for tuberculosis. Australian Prescriber. 2010;33(1):12-8.
  4. Dye C, Scheele S, gt, Dolin P, Pathania V, Raviglione MC. Global Burden of Tuberculosis. JAMA. 1999;282(7):677.
  5. Zhang YaY, W. Mechanisms of drug resistance in Mycobacterium tuberculosis. The International Journal of Tuberculosis and Lung Disease. 2009;13(11):1320-30.
  6. Jadhav S, Fatema S, S. Bhagat S, Farooqui M. Thiazolo[3,2‐a] Pyrimidones as a Novel Anti‐TB Agents. 2018;55:2893-900.
  7. Chetty S, Armstrong T, Sharma Kharkwal S, Drewe WC, De Matteis CI, Evangelopoulos D, 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.
  8. Timmins GS, Deretic V. Mechanisms of action of isoniazid. Molecular Microbiology. 2006;62(5):1220-7.
  9. Zhang Y, Yew WW. Mechanisms of drug resistance in Mycobacterium tuberculosis: update 2015. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease. 2015;19(11):1276-89.
  10. Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a review. The international journal of tuberculosis and lung disease. 2003;7(1):6-21.
  11. Takayama K, Kilburn JO. Inhibition of synthesis of arabinogalactan by ethambutol in Mycobacterium smegmatis. Antimicrob Agents Chemother. 1989;33(9):1493-9.
  12. Palomino JC, Martin A. Drug Resistance Mechanisms in Mycobacterium tuberculosis. Antibiotics (Basel, Switzerland). 2014;3(3):317-40.
  13. Aubry A, Pan XS, Fisher LM, Jarlier V, Cambau E. Mycobacterium tuberculosis DNA gyrase: interaction with quinolones and correlation with antimycobacterial drug activity. Antimicrob Agents Chemother. 2004;48(4):1281-8.
  14. Alangaden GJ, Kreiswirth BN, Aouad A, Khetarpal M, Igno FR, Moghazeh SL, et al. Mechanism of resistance to amikacin and kanamycin in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 1998;42(5):1295-7.
  15. Deoghare S. Bedaquiline: a new drug approved for treatment of multidrug-resistant tuberculosis. Indian journal of pharmacology. 2013;45(5):536-7.
  16. Xavier AS, Lakshmanan M. Delamanid: A new armor in combating drug-resistant tuberculosis. Journal of pharmacology & pharmacotherapeutics. 2014;5(3):222-4.
  17. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-resistant-forms-tuberculosis-affects-lungs#:~:text=The%20U.S.%20Food%20and%20Drug,(TB)%20of%20the%20lungs, accessed in February 2023.
  18. Conradie F, Bagdasaryan TR, Borisov S, Howell P, Mikiashvili L, Ngubane N, et al. Bedaquiline–pretomanid–linezolid regimens for drug-resistant tuberculosis. New England Journal of Medicine. 2022;387(9):810-23.
  19. Gualano G, Capone S, Matteelli A, Palmieri F. New antituberculosis drugs: from clinical trial to programmatic use. Infectious Disease Reports. 2016;8(2):6569.
  20. Sridhar A, Sandeep Y, Krishnakishore C, Sriramnaveen P, Manjusha Y, Sivakumar V. Fatal poisoning by isoniazid and rifampicin. Indian J Nephrol. 2012;22(5):385-7.
  21. Fox GJ, Menzies D. A Review of the Evidence for Using Bedaquiline (TMC207) to Treat Multi-Drug Resistant Tuberculosis. Infectious Diseases and Therapy. 2013;2(2):123-44.
  22. De Souza MVN, Ferreira MdL, Pinheiro AC, Saraiva MF, de Almeida MV, Valle MS. Synthesis and biological aspects of mycolic acids: an important target against Mycobacterium tuberculosis. The scientific world journal. 2008;8:720-51.
  23. Prasad MS, Bhole RP, Khedekar PB, Chikhale RV. Mycobacterium enoyl acyl carrier protein reductase (InhA): A key target for antitubercular drug discovery. Bioorganic Chemistry. 2021;115:105242.
  24. 2019 MOE. https://www.chemcomp.com/Products.htm.
  25. Matviiuk T, Madacki J, Mori G, Orena BS, Menendez C, Kysil A, et al. Pyrrolidinone and pyrrolidine derivatives: Evaluation as inhibitors of InhA and Mycobacterium tuberculosis. European journal of medicinal chemistry. 2016;123:462-75.
  26. Kamsri P, Hanwarinroj C, Phusi N, Pornprom T, Chayajarus K, Punkvang A, et al. Discovery of new and potent inha inhibitors as antituberculosis agents: structure-based virtual screening validated by biological assays and x-ray crystallography. Journal of chemical information and modeling. 2019;60(1):226-34.
  27. Kuldeep J, Sharma SK, Sharma T, Singh BN, Siddiqi MI. Targeting Mycobacterium Tuberculosis Enoyl‐Acyl Carrier Protein Reductase Using Computational Tools for Identification of Potential Inhibitor and their Biological Activity. Molecular Informatics. 2021;40(5):2000211.
  28. Hassan S, Sudhakar V, Mary MBN, Babu R, Doble M, Dadar M, et al. Computational approach identifies protein off-targets for Isoniazid-NAD adduct: hypothesizing a possible drug resistance mechanism in Mycobacterium tuberculosis. Journal of Biomolecular Structure and Dynamics. 2019;38(6):1697-710.
  29. Ibrahim TS, Taher ES, Samir E, M Malebari A, Khayyat AN, Mohamed MF, et al. In Vitro Antimycobacterial Activity and Physicochemical Characterization of Diaryl Ether Triclosan Analogues as Potential InhA Reductase Inhibitors. Molecules. 2020;25(14):3125.
  30. Chebaiki M, Delfourne E, Tamhaev R, Danoun S, Rodriguez F, Hoffmann P, et al. Discovery of new diaryl ether inhibitors against Mycobacterium tuberculosis targeting the minor portal of InhA. European Journal of Medicinal Chemistry. 2023;259:115646.
  31. Tamhaev R, Grosjean E, Ahamed H, Chebaiki M, Rodriguez F, Recchia D, et al. Exploring the plasticity of the InhA substrate-binding site using new diaryl ether inhibitors. Bioorganic Chemistry. 2024;143:107032.
  32. Hartkoorn RC, Pojer F, Read JA, Gingell H, Neres J, Horlacher OP, et al. Pyridomycin bridges the NADH-and substrate-binding pockets of the enoyl reductase InhA. Nature chemical biology. 2014;10(2):96-8.
  33. Shaaban MM, Teleb M, Ragab HM, Singh M, Elwakil BH, A. Heikal L, et al. The first-in-class pyrazole-based dual InhA-VEGFR inhibitors towards integrated antitubercular host-directed therapy. Bioorganic Chemistry. 2024;145:107179.
  34. Rodriguez F, Saffon N, Sammartino JC, Degiacomi G, Pasca MR, Lherbet C. First triclosan-based macrocyclic inhibitors of InhA enzyme. Bioorganic chemistry. 2020;95:103498.
  35. Rozwarski DA. Modification of the NADH of the Isoniazid Target (InhA) from Mycobacterium tuberculosis. Science (New York, NY). 1998;279(5347):98-102.
  36. Tonge P, Kisker C, Slayden R. Development of Modern InhA Inhibitors to Combat Drug Resistant Strains of Mycobacterium tuberculosis. Current Topics in Medicinal Chemistry. 2007;7(5):489-98.
  37. Zhang Y, Yew W. Mechanisms of drug resistance in Mycobacterium tuberculosis: update 2015. The International Journal of Tuberculosis and Lung Disease. 2015;19(11):1276-89.
  38. Volynets GP, Tukalo MA, Bdzhola VG, Derkach NM, Gumeniuk MI, Tarnavskiy SS, et al. Novel isoniazid derivative as promising antituberculosis agent. Future Microbiology. 2020;15(10):869-79.
  39. Atta A, Fahmy S, Rizk O, Sriram D, Mahran MA, Labouta IM. Structure-based design of some isonicotinic acid hydrazide analogues as potential antitubercular agents. Bioorg Chem. 2018;80:721-32.
  40. Rožman K, Sosič I, Fernandez R, Young RJ, Mendoza A, Gobec S, et al. A new 'golden age' for the antitubercular target InhA. Drug discovery today. 2017;22(3):492-502.
  41. Vosátka R, Krátký M, Vinšová J. Triclosan and its derivatives as antimycobacterial active agents. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 2018;114:318-31.
  42. Kuo MR, Morbidoni HR, Alland D, Sneddon SF, Gourlie BB, Staveski MM, et al. Targeting tuberculosis and malaria through inhibition of Enoyl reductase: compound activity and structural data. The Journal of biological chemistry. 2003;278(23):20851-9.
  43. Menendez C, Gau S, Lherbet C, Rodriguez F, Inard C, Pasca MR, et al. Synthesis and biological activities of triazole derivatives as inhibitors of InhA and antituberculosis agents. European journal of medicinal chemistry. 2011;46(11):5524-31.
  44. Chollet A, Mori G, Menendez C, Rodriguez F, Fabing I, Pasca MR, et al. Design, synthesis and evaluation of new GEQ derivatives as inhibitors of InhA enzyme and Mycobacterium tuberculosis growth. European journal of medicinal chemistry. 2015;101:218-35.
  45. Bhat M, Belagali SL. Synthesis, characterization and biological screening of pyrazole-conjugated benzothiazole analogs. Future medicinal chemistry. 2018;10(1):71-87.
  46. Sabbah M, Mendes V, Vistal RG, Dias DM, Záhorszká M, Mikusova K, et al. Fragment-based design of Mycobacterium tuberculosis InhA inhibitors. Journal of medicinal chemistry. 2020;63(9):4749-61.
  47. Nalla V, Shaikh A, Bapat S, Vyas R, Karthikeyan M, Yogeeswari P, et al. Identification of potent chromone embedded [1,2,3]-triazoles as novel anti-tubercular agents. Royal Society open science. 2018;5(4):171750.
  48. Gaspar A, Matos MJ, Garrido J, Uriarte E, Borges F. Chromone: A Valid Scaffold in Medicinal Chemistry. Chemical Reviews. 2014;114(9):4960-92.
  49. Keri RS, Budagumpi S, Pai RK, Balakrishna RG. ChemInform Abstract: Chromones as a Privileged Scaffold in Drug Discovery: A Review. ChemInform. 2014;45(27):340–74.
  50. Reis J, Gaspar A, Milhazes N, Borges F. Chromone as a Privileged Scaffold in Drug Discovery: Recent Advances. Journal of Medicinal Chemistry. 2017;60(19):7941-57.
  51. de Carvalho da Silva F, Cardoso MFdC, Ferreira PG, Ferreira VF. Biological Properties of 1H-1,2,3- and 2H-1,2,3-Triazoles. Topics in Heterocyclic Chemistry: Springer International Publishing; 2014. p. 117-65.
  52. Xu Z, Song X-F, Hu Y-Q, Qiang M, Lv Z-S. Azide-alkyne cycloaddition towards 1H-1,2,3-triazole-tethered gatifloxacin and isatin conjugates: Design, synthesis and in vitro anti-mycobacterial evaluation. European Journal of Medicinal Chemistry. 2017;138:66-71.
  53. Zhang S, Xu Z, Gao C, Ren Q-C, Chang L, Lv Z-S, et al. Triazole derivatives and their anti-tubercular activity. European Journal of Medicinal Chemistry. 2017;138:501-13.
  54. Zhou B, He Y, Zhang X, Xu J, Luo Y, Wang Y, et al. Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents. Proceedings of the National Academy of Sciences. 2010;107(10):4573-8.
  55. Boechat N, Ferreira VF, Ferreira SB, Ferreira MdLG, da Silva FdC, Bastos MM, et al. Novel 1, 2, 3-triazole derivatives for use against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain. Journal of medicinal chemistry. 2011;54(17):5988-99.
  56. Shaikh MH, Subhedar DD, Arkile M, Khedkar VM, Jadhav N, Sarkar D, et al. Synthesis and bioactivity of novel triazole incorporated benzothiazinone derivatives as antitubercular and antioxidant agent. Bioorganic & medicinal chemistry letters. 2016;26(2):561-9.
  57. He X, Alian A, Ortiz de Montellano PR. Inhibition of the Mycobacterium tuberculosis enoyl acyl carrier protein reductase InhA by arylamides. Bioorganic & medicinal chemistry. 2007;15(21):6649-58.
  58. Karrouchi K, Radi S, Ramli Y, Taoufik J, Mabkhot Y, Al-aizari F, et al. Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review. Molecules. 2018;23(1):134.
  59. Pathak RB, Chovatia PT, Parekh HH. Synthesis, antitubercular and antimicrobial evaluation of 3-(4-chlorophenyl)-4-substituted pyrazole derivatives. Bioorganic & Medicinal Chemistry Letters. 2012;22(15):5129-33.
  60. Xu Z, Gao C, Ren Q-C, Song X-F, Feng L-S, Lv Z-S. Recent advances of pyrazole-containing derivatives as anti-tubercular agents. European Journal of Medicinal Chemistry. 2017;139:429-40.
  61. Hassan NW, Saudi MN, Abdel-Ghany YS, Ismail A, Elzahhar PA, Sriram D, et al. Novel pyrazine based anti-tubercular agents: design, synthesis, biological evaluation and in silico studies. Bioorganic chemistry. 2020;96:103610.
  62. Jadhav SB, Fatema S, Bhagat SS, Farooqui M. Thiazolo[3,2‐ a ] Pyrimidones as a Novel Anti‐TB Agents. Journal of Heterocyclic Chemistry. 2018;55(12):2893-900.
  63. Jadhav SB, Fatema S, Sanap G, Farooqui M. Antitubercular Activity and Synergistic Study of Novel Pyrazole Derivatives. Journal of Heterocyclic Chemistry. 2018;55(7):1634-44.

Files

Share

How to cite

Statistics