Novel 2-mercaptoquinazolinone N-hydroxycinnamamides as histone deacetylase inhibitors: design, synthesis, and anticancer evaluation.

Histone deacetylases (HDACs) are key therapeutic targets in oncology, and hydroxamic acid derivatives represent one of the most effective inhibitor classes. To explore the structure-activity relationships of this scaffold, a series of 2-mercaptoquinazoline-based hydroxamic acid derivatives (4a-e, 7a-i, and 10a-e) were synthesized and evaluated for HDAC inhibition and anticancer activity, with SAHA serving as a positive control. The 4a-e series emerged as the most potent HDAC inhibitors, with IC50 values of 0.33-0.87 μM, led by 4a (0.33 ± 0.02 μM), though weaker than SAHA (0.06 ± 0.01 μM). Cytotoxicity assays across colorectal (SW620, HCT116), breast (MDA-MB-231), prostate (PC-3), and lung (A549) cancer cell lines demonstrated that 4b (6-CH3) and 4c (7-CH3) were the most effective, achieving IC50 values of 0.93-1.34 μM in HCT116 and 1.79-2.08 μM in SW620. In the 7a-i series, compounds 7b (6-CH3), 7d (6-Cl), and particularly 7f (7-F) demonstrated notable cytotoxicity with IC50 values of 1.14-3.64 μM across SW620, HCT116, and MDA-MB-231 cells, comparable to the most active derivatives in the 4-series; conversely, bulky halogen substituents (7g, 7i) or the unsubstituted analog 7a led to markedly reduced activity (> 4.5 μM). The 10a-e series was significantly less active, and 10e (7-F) showed undesirable toxicity toward normal MRC-5 fibroblasts (IC50 = 0.72 ± 0.02 μM). Mechanistic studies further confirmed that 4c and 7f induced G2/M arrest and apoptosis in SW620 cells. Collectively, these findings highlight 4a-c and 7f as promising lead compounds, combining submicromolar HDAC inhibition, potent antiproliferative effects, and acceptable selectivity, providing a strong foundation for further development of quinazoline-based HDAC inhibitors. Molecular docking studies supported these results by revealing favorable interactions of the hydroxamate zinc-binding group and the 2-mercaptoquinazoline scaffold within the HDAC active site, consistent with the observed structure-activity relationship (SAR) trends.