Stable isoniazid derivatives: In silico studies, synthesis and biological assessment against mycobacterium tuberculosis in liquid culture

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Rasayan Journal of Chemistry


Isoniazid (INH) is well-known as a crucial drug in all multiple drug treatment for tuberculosis (TB) as approved by the WHO. It is a small molecule and highly hydrophilic, has low cellular penetration. By modifying highly hydrophilic drugs into hydrophobic will help in enhancing the cellular penetration of the drug and this, in turn, improves the therapeutic efficacy of the drug. Isoniazid a prodrug gets activated by KatG enzyme of Mycobacterium tuberculosis thus inhibiting InhA enzyme essential for the synthesis of Mycolic acid, a chief component of Mycobacterium tuberculosis cell wall. Hence in the current study, a series of isoniazid hydrazones are designed where Isoniazid can be modified to make it more stable in basic pH condition and InhA protein is identified as a potential drug target for Isoniazid derivatives to study the anti-tuberculosis activity. Active hydrazones were synthesized and characterized by modern analytical techniques and evaluated for their anti-tubercular activities. Antimicrobial susceptibility test (AST) against Mycobacterium tuberculosis was assessed using a different method Mycobacteria Growth Indicator Tube (MGIT™) 960 on a BACTEC system using molar equivalent concentrations of synthesized derivatives as recommended for minimal inhibitory concentration (MIC) of Isoniazid. The compounds in which INH modified with hydrophobic groups exhibited anti-tubercular activity on the H37Rv strain of Mycobacterium tuberculosis. The stability studies revealed that the synthesized INH derivatives were more stable than standard drug Isoniazid in basic pH conditions. MTT assay confirmed that synthesized active compounds do not pose any cytotoxic effect on RAW 264.7 macrophage cell line.

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