A comprehensive review on azole-based hydroxamic acid analogs as histone deacetylases (HDACs) inhibitors.

BACKGROUND

Histone deacetylases (HDAC) are essential epigenetic enzymes that modulate the remodeling of chromatin and transcriptional activity. Overexpression of HDAC has been associated with tumorigenesis, angiogenesis, metastasis, and therapeutic resistance.

METHODS

A systematic survey (2008-2025) evaluated the design, mechanism, and structure-activity relationships (SAR) of azole-based hydroxamic acid (ABHA) derivatives as histone deacetylase inhibitors (HDACIs).

RESULTS

ABHAs containing 1,3,4-oxadiazole, pyrazole, imidazole, triazole, indazole, thiadiazole, etc. Heterocyclic scaffolds show significant zinc-binding affinity, enhanced pharmacokinetics, and isoform-selective inhibition. Subtle structural variations in heteroaryl substituents, linker architecture, and hydroxamate coordination significantly modulate enzyme selectivity and cytotoxic efficacy.

CONCLUSION

ABHA hybrids provide versatile scaffolds with diverse activity for the rational development of next-generation, isoform-selective HDACIs with enhanced potency and therapeutic promise in anticancer drug design.