Novel quinazoline-triazole-based <i>N</i>-hydroxybenzamides/<i>N</i>-hydroxypropenamides as HDAC inhibitors: design, synthesis, biological evaluation, and docking studies

Herein, two novel series of <i>N</i>-hydroxybenzamides and <i>N</i>-hydroxypropenamides incorporating 4-oxoquinazoline and 1,2,3-triazole scaffolds were rationally designed, synthesized, and evaluated for their Histone deacetylase (HDAC) inhibitory and anticancer activities. The synthesized hydroxamic acids were evaluated for HDAC inhibitory activity using nuclear extracts from HeLa cells. <i>N</i>-hydroxybenzamide derivatives (7a-i) exhibited stronger HDAC inhibition than their <i>N</i>-hydroxypropenamide counterparts (11a-i). Compounds 7h (7-Br) and 7c (7-CH₃) were the most potent inhibitors, with IC₅₀ values of 0.142 and 0.146 μM, respectively, which are comparable to that of the positive control, SAHA. Structural modifications at positions 6 and 7 of the quinazoline core significantly influenced activity. For CH₃- and Br-substituted derivatives, substitution at position 7 enhanced HDAC inhibition, whereas for fluorinated derivatives, 6-F (7e) was more potent than 7-F (7f). Similar trends were observed in the <i>N</i>-hydroxypropenamide series, with some exceptions. Cytotoxicity studies against cancer cells (such as SW620 and MDA-MB-231) revealed that <i>N</i>-hydroxypropenamide derivatives generally had stronger antiproliferative effects. The 6-Cl derivatives (7d, 11d) exhibited the highest cytotoxic activity, highlighting the significance of halogen substitution. Selectivity assessments against normal human lung fibroblasts (MRC-5) indicated that most compounds were more toxic to cancer cells. Notably, 7d and 11d induced G2/M phase arrest and apoptosis, demonstrating their potential as HDAC inhibitors with promising anticancer properties. Finally, molecular docking studies on HDAC isoforms for the 7a-i and 11a-i series revealed key structural features crucial for the activity of the library compounds.