• Ji Hyun Kim, Khan Hashim Ali, Yong Jin Oh, and Young Ho Seo.
• College of Pharmacy, Keimyung University, Daegu, Republic of Korea.
• Medicine (Baltimore). 2022 Apr 29; 101 (17): e29049e29049.

IntroductionHistone deacetylases (HDACs) have emerged as important therapeutic targets for various diseases, such as cancer and neurological disorders. Although a majority of HDAC inhibitors use hydroxamic acids as zinc binding groups, hydroxamic acid zinc-binding groups suffer from poor bioavailability and nonspecific metal-binding properties, necessitating a new zinc-binding group. Salicylic acid and its derivatives, well-known for their therapeutic value, have also been reported to chelate zinc ions in a bidentate fashion. This drew our attention towards replacing hydroxamic acid with salicylamide as a zinc-binding group.MethodsIn this study, for the first time, compound 5 possessing a novel salicylamide zinc-binding group was synthesized and evaluated biologically for its ability to inhibit various HDAC isoforms and induce acetylation upon α-tubulin and histone H3 among MDA-MB-231 cells.ResultsCompound 5 exhibits selective inhibition against class I HDAC isoforms (HDAC1, 2, and 3) over class II and IV HDAC isoforms (HDAC4, 6, and 11). The exposure of MDA-MB-231 cells to compound 5 efficiently induced the acetylation of more histone H3 than α-tubulin, suggesting that compound 5 is a class I selective HDAC inhibitor. Moreover, the molecular docking study indicated that the salicylamide zinc-binding group of compound 5 coordinates the active zinc ion of class I HDAC2 in a bidentate fashion.ConclusionOverall, salicylamide represents a novel zinc-binding group for the development of class I selective HDAC inhibitors.Graphical Abstract(http://links.lww.com/MD/G668).Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.

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