Structure elaboration of isoniazid: synthesis, in silico molecular docking and antimycobacterial activity of isoniazid–pyrimidine conjugates
Designing small molecule-based new drug candidates through structure modulation of the existing drugs has drawn considerable attention in view of inevitable emergence of resistance. A new series of isoniazid–pyrimidine conjugates were synthesized in good yields and evaluated for antitubercular activity against the H37Rv strain of Mycobacterium tuberculosis using the microplate Alamar Blue assay. Structure–anti-TB relationship profile revealed that conjugates 8a and 8c bearing a phenyl group at C-6 of pyrimidine scaffold were most active (MIC99 10 µM) and least cytotoxic members of the series. In silico docking of 8a in the active site of bovine lactoperoxidase as well as a cytochrome C peroxidase mutant N184R Y36A revealed favorable interactions similar to the heme enzyme catalase peroxidase (KatG) that activates isoniazid. This investigation suggests a rationale for further work on this promising series of antitubercular agents.
KeywordsIsoniazid Pyrimidine Conjugates Tuberculosis Drug resistance Molecular docking ADME
Microplate Alamar Blue assay
World Health Organization
Sustainable development goals
Heme (ferric) enzyme catalase peroxidase
2-trans-enoyl-acyl carrier protein reductase
Adsorption, distribution, metabolism, excretion
We gratefully acknowledge financial assistance from CSIR, New Delhi (Project 02(0268)/16/EMR-II). We also thank Ronnett Seldon and Dale Taylor for antimycobacterial and cytotoxicity screening, respectively. KS thanks Schrodinger, India, for complimentary license.
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
- 2.Monge-Maillo B, Lopez-Velez R, Norman FF, Ferrere-Gonzalez F, Martınez-Perez A, Perez-Molina JA (2015) Screening of imported infectious diseases among asymptomatic sub-Saharan African and Latin American immigrants: a public health challenge. Am J Trop Med Hyg 92:848–856CrossRefPubMedPubMedCentralGoogle Scholar
- 5.Global Tuberculosis report 2018, WHOGoogle Scholar
- 12.Zumla A, Chakaya J, Centis R, D’Ambrosio L, Mwaba P, Bates M, Kapata N, Nyirenda T, Chanda D, Mfinanga S, Hoelscher M, Maeurer M, Migliori GB (2015) Tuberculosis treatment and management–an update on treatment regimens, trials, new drugs, and adjunct therapies. Lancet Respir Med 3:220–234CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Bass Jr JB, Farer LS, Hopewell PC, O’Brien R, Jacobs RF, Ruben F, Snider Jr DE, Thornton GS (1994) Treatment of tuberculosis and tuberculosis infection in adults and children. American Thoracic Society and The Centers for Disease Control and Prevention. Am J Respir Crit Care Med 149:1359–1374CrossRefGoogle Scholar
- 26.Varano F, Catarzi D, Vincenzi F, Betti M, Falsini M, Ravani A, Borea PA, Colotta V, Varani K (2016) Design, synthesis, and pharmacological characterization of 2-(2-Furanyl)thiazolo[5,4-d]pyrimidine-5,7-diamine derivatives: new highly potent A2A adenosine receptor inverse agonists with antinociceptive activity. J Med Chem 59:10564–10576CrossRefGoogle Scholar
- 27.Bookser BC, Ugarkar BG, Matelich MC, Lemus RH, Allan M, Tsuchiya M, Nakane M, Nagahisa A, Wiesner JB, Erion MD (2005) Adenosine kinase inhibitors. 6. Synthesis, water solubility, and antinociceptive activity of 5-phenyl-7-(5-deoxy-β-d-ribofuranosyl)pyrrolo[2,3-d]pyrimidines substituted at C4 with glycinamides and related compounds. J Med Chem 48:7808–7820CrossRefGoogle Scholar
- 34.Singh K, Singh K, Wan B, Franzblau S, Chibale K, Balzarini J (2011) Facile transformation of Biginelli pyrimidin-2(1H)-ones to pyrimidines. In vitro evaluation as inhibitors of Mycobacterium tuberculosis and modulators of cytostatic activity. Eur J Med Chem 46:2290–2294CrossRefPubMedPubMedCentralGoogle Scholar
- 36.Chatterji M, Shandil R, Manjunatha MR, Solapure S, Ramachandran V, Kumar N, Saralaya R, Panduga V, Reddy J, Prabhakar KR, Sharma S, Sadler C, Cooper CB, Mdluli K, Iyer PS, Narayanan S, Shirude PS (2014) 1, 4-Azaindole, a potential drug candidate for treatment of tuberculosis. Antimicrob Agents Chemother 58:5325–5331CrossRefPubMedPubMedCentralGoogle Scholar
- 37.Biginelli P, Gazz P (1893) Synthesis of 3,4-Dihydropyrimidin-2(1H)-Ones. Chim Ital 23:360–416Google Scholar
- 38.Singh K (2012) Biginelli condensation: synthesis and structure diversification of 3,4-dihydropyrimidin-2(1H)-one derivatives. In: Katritzky AR (ed) Advances in heterocyclic chemistry, vol 105. Academic Press, Cambridge, pp 223–308Google Scholar
- 40.Falsone FS, Kappe CO (2001) The Biginelli dihydropyrimidone synthesis using polyphosphate ester as a mild and efficient cyclocondensation/dehydration reagent. Arkivoc 2:122–134Google Scholar
- 45.Singh AK, Kumar RP, Pandey N, Singh N, Sinha M, Bhushan A, Kaur P, Sharma S, Singh TP (2010) Mode of binding of the tuberculosis prodrug isoniazid to heme peroxidases: binding studies and crystal structure of bovine lactoperoxidase with isoniazid at 2.7 A resolution. J Biol Chem 285:1569–1576CrossRefPubMedPubMedCentralGoogle Scholar