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

Kaur, H
Singh, L
Chibale, K
Singh, K
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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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Date
2019-10-18
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Publisher
Springer Nature
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Keywords
ADME,Conjugates,Drug resistance,Isoniazid,Molecular docking,Pyrimidine
Citation
Kaur H, Singh L, Chibale K, Singh K. Structure elaboration of isoniazid: synthesis, in silico molecular docking and antimycobacterial activity of isoniazid-pyrimidine conjugates. Mol Divers. 2020 Nov;24(4):949-955. doi: 10.1007/s11030-019-10004-1.
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