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

  • Hardeep Kaur
  • Lovepreet Singh
  • Kelly Chibale
  • Kamaljit SinghEmail author
Original Article


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.

Graphic abstract


Isoniazid Pyrimidine Conjugates Tuberculosis Drug resistance Molecular docking ADME 



Microplate Alamar Blue assay


World Health Organization


Sustainable development goals










Polyphosphate ester


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.

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Supplementary material

11030_2019_10004_MOESM1_ESM.docx (3.9 mb)
Full experimental details (including 1HNMR/13CNMR/MS spectra, etc.) for the synthesized compounds, synthetic procedures and procedures for in vitro antitubercular assay, cytotoxicity and antiviral assay. Table S1 for ADME predictions (PDF). (DOCX 4021 kb)


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Chemistry, UGC Centre of Advance Study-IIGuru Nanak Dev UniversityAmritsarIndia
  2. 2.South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular MedicineUniversity of Cape TownRondeboschSouth Africa

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