Structure elaboration of isoniazid: synthesis, in silico molecular docking and antimycobacterial activity of isoniazid–pyrimidine conjugates

Abstract

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.

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Abbreviations

MABA:

Microplate Alamar Blue assay

WHO:

World Health Organization

SDG:

Sustainable development goals

INH:

Isoniazid

RIF:

Rifampicin

PZA:

Pyrazinamide

EMB:

Ethambutol

PPE:

Polyphosphate ester

KatG:

Heme (ferric) enzyme catalase peroxidase

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide

InhA:

2-trans-enoyl-acyl carrier protein reductase

ADME:

Adsorption, distribution, metabolism, excretion

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Acknowledgements

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.

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Correspondence to Kamaljit Singh.

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Kaur, H., Singh, L., Chibale, K. et al. Structure elaboration of isoniazid: synthesis, in silico molecular docking and antimycobacterial activity of isoniazid–pyrimidine conjugates. Mol Divers 24, 949–955 (2020). https://doi.org/10.1007/s11030-019-10004-1

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Keywords

  • Isoniazid
  • Pyrimidine
  • Conjugates
  • Tuberculosis
  • Drug resistance
  • Molecular docking
  • ADME