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Key structural requirements of benzamide derivatives for histone deacetylase inhibition: design, synthesis and biological evaluation.
Future Medicinal Chemistry 2024 April 17
Background: Histone deacetylase inhibitors (HDACIs) are important as anticancer agents. Objective: This study aimed to investigate some key structural features of HDACIs via the design, synthesis and biological evaluation of novel benzamide-based derivatives. Methods: Novel structures, designed using a molecular modification approach, were synthesized and biologically evaluated. Results: The results indicated that a subset of molecules with CH3 /NH2 at R2 position possess selective antiproliferative activity. However, only those with an NH2 group showed HDACI activity. Importantly, the shorter the molecule length, the stronger HDACI. Among all, 7j was the most potent HDAC1-3 inhibitor and antiproliferative compound. Conclusion: The results of the present investigation could provide valuable structural knowledge applicable for the development of the HDACIs and benzamide-based antiproliferative agents in the future.
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