Role of Different Isoniazid Analogs as Antitubercular Agents

Abstract— Tuberculosis (TB) remains one of the world’s deadliest infectious diseases. It is also a leading cause of mortality among people living with HIV, accounting for one in three HIV-related deaths. The emergence and spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis strains now threaten global TB control efforts. Current therapies require prolonged, multi-drug regimens that often lead to severe adverse effects and poor adherence, which further drive resistance. Isoniazid (INH) remains the cornerstone of first-line TB treatment, but its utility is compromised by resistance and hepatotoxicity—particularly in fast acetylators. To overcome these limitations, researchers have designed a variety of lipophilic INH analogs and hybrids, incorporating heterocyclic scaffolds (e.g., pyrazole, triazine, quinoline) to enhance cell-wall penetration and metabolic stability. Several of these compounds, including the cyclized derivative LL-3858, have advanced to preclinical and early clinical evaluation, demonstrating potent activity against drug-resistant strains and reduced toxicity profiles. This review summarizes the structural modifications of INH, highlights the most promising analogs and hybrids, and discusses their mechanisms of action, pharmacokinetics, and in vitro/in vivo efficacy. By offering shorter, safer, and more effective regimens, next-generation INH derivatives hold promise as key tools in the fight against MDR- and XDR-TB—especially in settings burdened by HIV co-infection—and may soon be poised for approval by regulatory authorities.