Antitubercular Activity Evaluation of Isoniazid Derivatives
Summary
Tuberculosis remains a leading cause of mortality worldwide, exacerbated by the emergence of drug-resistant strains of Mycobacterium tuberculosis. Isoniazid (INH) has long been a cornerstone of first-line therapy, owing to its potent inhibition of the enoyl-acyl carrier protein reductase InhA and consequent block of mycolic acid biosynthesis. However, mutations in katG and inhA, together with pharmacokinetic limitations such as poor membrane permeability, have driven efforts to engineer novel INH derivatives. Research in this field encompasses the design and synthesis of hydrazide and hydrazone analogues, mechanochemical approaches to reduce solvent use, and systematic structure–activity relationship (SAR) studies. Antitubercular potency is typically assessed by minimum inhibitory concentration (MIC) assays against drug-susceptible and multidrug-resistant (MDR) strains, coupled with selectivity indexes from cytotoxicity evaluations. Key aims include enhancing lipophilicity to improve cell uptake, moderating radical formation kinetics to avoid excessive reactivity, and preserving or augmenting target engagement with InhA. This multifaceted strategy promises improved therapeutic profiles, reduced resistance emergence and broader global applicability.
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Antitubercular Activity Evaluation of Isoniazid Derivatives publication trend
The graph below shows the total number of articles in antitubercular activity evaluation of isoniazid derivatives across all publications each year (not limited to Nature Index journals).
Technical terms
Isoniazid (INH): A hydrazide scaffold and first-line antitubercular drug that inhibits InhA.
Minimum inhibitory concentration (MIC): The lowest concentration of a compound that prevents visible microbial growth in vitro.
Multidrug-resistant (MDR): Mycobacterial strains resistant to at least isoniazid and rifampicin.
InhA: Enoyl-acyl carrier protein reductase, the enzymatic target of isoniazid in mycolic acid biosynthesis.
Structure–activity relationship (SAR): Analysis linking chemical structure modifications with changes in biological activity.
Hydrazone: A functional group (–C=NNH–) formed from hydrazide derivatives, often used to modulate pharmacokinetic properties.
Lipophilicity: A measure of a compound’s affinity for lipid environments, influencing membrane permeability.
Selectivity index (SI): The ratio of cytotoxic concentration to antimicrobial effective concentration, indicating compound safety.
References
- Mechanochemical Synthesis and Biological Evaluation of Novel Isoniazid Derivatives with Potent Antitubercular Activity. Molecules (2017).
- Designing new antitubercular isoniazid derivatives with improved reactivity and membrane trafficking abilities. Biomedicine & Pharmacotherapy (2021).
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