Advancements in Isoniazid-Based Heterocyclic Derivatives as Potent Antitubercular Agents: A Comprehensive Review of Synthesis, SAR, and Biological Activity (2017-2023)

Tuberculosis (TB) continues to be a major health problem worldwide, requiring the development of new and innovative therapeutic agents. Isoniazid (INH) is one of the drugs of choice for treating tuberculosis. It is activated by KatG, which produces nicotinamide ade-nine dinucleotide (NAD). The resulting metabolites inhibit enoyl-acylcarrier protein (ACP) reductase (InhA), an enzyme involved in the bio-synthesis of mycolic acid in Mycobacterium tuberculosis. This inhibitiondisrupts the production of type II fatty acids, which are essential for my-colic acid synthesis and cell survival. However, INH-resistant mycobac-terial strains are becoming more prevalent, primarily due to long-term,widespread use and misuse. Researchers have extensively researchedand modified INH, a cornerstone in TB treatment, to improve its effica-cy and reduce resistance. Numerous investigations have shown thatheterocyclic scaffolds, when coupled with INH, exhibit excellent antitu-bercular activity by increasing the permeation of the drug into bacterialcells. The review highlights various heterocyclic moieties, includingp henylisoxazole, indanyl, indole, and isatin, emphasizing their role inimproving pharmacokinetic properties and overcoming drug resistance. Here, we have focused on INH-clubbed heterocyclic derivativesthat were investigated from 2018 to 2023 as potential antitubercularagents. This review aims to guide future research and development ofINH-based heterocyclic derivatives, offering a valuable resource for re-searchers in the quest for more effective antitubercular therapies