Design, synthesis, and bioevaluation of 1H-1,2,3-triazole-linked quinazolin-4(3H)-one hydroxamic acids as novel histone deacetylase inhibitors

Abstract

Histone deacetylases (HDACs) are pivotal epigenetic regulators implicated in cancer progression. Inhibition of HDACs represents a promising direction in therapeutic development. In this study, hydroxamic acids bearing 4-oxoquinoline and 1,2,3-triazole scaffolds were synthesized and evaluated for their cytotoxic effects on three cell lines: SW620 (colon cancer), MDA-MB-231 (breast cancer), and MRC-5 (human fetal lung fibroblasts), using SAHA as a reference compound. The results indicate that the length of alkyl σ-linkers critically influences the cytotoxic activity of these compounds. Notably, the N-hydroxyheptanamide series with a 6-carbon linker demonstrated the strongest cytotoxic effects against the cancer cell lines, while the N-hydroxybutanamide series demonstrated that the 1,2,3-triazole ring may serve partially as a linker, aligning with the HDAC active site channel dimensions. Structural modifications at positions 6 and 7 further modulated activity: in the N-hydroxybutanamide derivatives (19a？i), halogen substitutions revealed distinct structure？activity relationships, with 7-F and 6-Br derivatives showing superior potency and selectivity in certain cases. Similarly, modifications in series 22a？i underscored the favorable impact of 6-Cl and 6-Br substitutions on cytotoxicity, while smaller halogens provided intermediate activity. Based on cytotoxicity assays and subsequent HDAC inhibition evaluation using HeLa cell extracts, compound 22g emerged as a lead candidate, exhibiting strong HDAC inhibitory potency (IC50 = 0.471 μM) and promising antiproliferative effects. Further mechanistic studies on 22g demonstrated its significant impact on cell cycle progression and apoptosis in SW620 colon cancer cells. Finally, molecular docking analyses of HDAC isoforms for the 22a-i series uncovered essential structural elements that are pivotal for the inhibitory efficacy of the library compounds.