Exploration of 2-Mercaptoquinazolin-4(3H)-one Based N-Hydroxyheptanamides as Histone Deacetylase Inhibitors: Design, Synthesis, and Anticancer Bioevaluation.

OBJECTIVE

Histone deacetylase (HDAC) inhibitors have emerged as promising cancer therapeutics by regulating gene expression, halting cell cycle progression, and inducing apoptosis. This study explores the structure-activity relationship of 2-mercaptoquinazolin-4(3H)-one derivatives as potential anticancer agents and HDAC inhibitors.

METHODS

The library compounds were prepared via a three-step pathway by incorporating 2-mercaptoquinazoline and a hydroxamic acid moiety. The cytotoxicity of 27 synthesized hydroxamic acid derivatives was evaluated against SW620 (colon cancer), MDA-MB-231 (breast cancer), and MRC-5 (normal lung fibroblast) cell lines. Molecular docking studies on HDAC-isoforms for the 4a-i were also performed to identify the essential structural features that contribute to the biological activities.

RESULTS

The results demonstrated that substituents at the N-3 position significantly influenced anticancer activity, with methyl-substituted derivatives (4a-i) exhibiting the highest cytotoxicity, followed by phenyl-substituted (7a-i) and benzyl-substituted (10a-i) compounds. Among the tested compounds, 4a (-H) and 4c (7-CH₃) showed as the most potent active compounds, with IC50 values of 4.24 ± 1.16 µM and 3.61 ± 0.32 µM against SW620 cells, and 2.93 ± 0.68 µM and 3.34 ± 0.32 µM against MDA-MB-231 cells, respectively. HDAC inhibition assays revealed that 4a-d and 4 g exhibited superior inhibitory activity compared to SAHA. Further investigation of 4a and 4c in SW620 cells showed that both compounds induced G2/M phase cell cycle arrest and promoted apoptosis, supporting their potential as promising HDAC inhibitors with anticancer properties.

CONCLUSIONS

Among the most active compounds, 4a and 4c may serve as promising leads for the development of novel HDAC-targeted anticancer therapies.