Chromone-Based Hybrids as Next-Generation Anti-Tubercular Agents: Design Strategies, Mechanisms, and Therapeutic Potential

Abstract

Tuberculosis (TB) remains a critical global health challenge with 10.6 million new cases and 1.3 million deaths reported in 2022. The emergence of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains, affecting approximately 410,000 individuals with only 41% receiving appropriate treatment, necessitates innovative therapeutic strategies. This review evaluates chromone-based hybrid molecules as next-generation anti-tubercular agents, analyzing design strategies, structure-activity relationships, and preclinical validation from studies published between 2013-2023. The chromone (1,4-benzopyran-4-one) scaffold demonstrates exceptional versatility through its rigid planar architecture, enabling multi-target engagement against critical mycobacterial enzymes including InhA, DprE1, DNA gyrase, and ATP synthase. Strategic hybridization utilizing triazole, amide, urea, and sulfonamide linkers yielded compounds with minimum inhibitory concentrations of 0.08-0.50 μg/mL against drug-sensitive and resistant Mycobacterium tuberculosis strains. Lead chromone-isoniazid conjugates achieved MICs of 0.15-0.35 μg/mL with selectivity indices exceeding 60, while chromone-triazole derivatives demonstrated dual InhA/DprE1 inhibition with IC₅₀ values of 0.08-0.25 μM. Optimized hybrids exhibited excellent oral bioavailability (45-82%), appropriate elimination half-lives (6.9-11.2 hours), and exceptional lung targeting with lung-to-plasma ratios of 8-15:1. In murine infection models, lead candidates achieved 1.8-2.5 log₁₀ CFU reductions in lung tissue with minimal toxicity. Integration of computational optimization, green synthesis methodologies, and advanced delivery systems positions chromone hybrids as promising candidates for clinical development, offering multi-target selectivity and reduced resistance potential critical for addressing the global tuberculosis crisis.