Spiro[indoline-tetrazolo[1,5-c]quinazoline] derivatives as candidate HDAC8 inhibitors: a molecular docking and ADMET analysis using the HDAC8–inhibitor complex (PDB 2V5X)

<title>Abstract</title> <p> Histone deacetylase 8 (HDAC8) represents a promising therapeutic target for Cornelia de Lange syndrome and certain cancers. This study investigates novel spiro[indoline-tetrazolo[1,5- <italic>c</italic> ]quinazoline] derivatives as HDAC8 inhibitors through molecular docking using the 2V5X HDAC8–inhibitor crystal structure, with preliminary cytotoxicity assessment of related compounds. Lead compounds KB-282 and KB-281 yielded docking scores of − 12.3 and − 11.0 kcal/mol, respectively, exceeding the docking scores obtained for the established HDAC8-selective reference inhibitors under identical conditions. Structure-activity relationship analysis identified critical pharmacophoric elements: carboxamide/carbothioamide groups at position 1 of the indoline ring and electron-withdrawing substituents on the phenyl ring. Preliminary cytotoxicity assessment of related compounds (KB-268, KB-270, KB-292) was consistent with the computational ranking, with KB-270 exhibiting moderate cytotoxic activity (IC₅₀ 34.88–49.69 µM) while lower-binding compounds showed minimal activity (IC₅₀ &gt;50 µM). Unlike conventional hydroxamate inhibitors, these compounds employ π-interactions with aromatic residues (Phe152, Phe208, Tyr306) and electrostatic interactions with Asp101 rather than zinc chelation. This non-hydroxamate mechanism may confer advantages in isoform selectivity and could reduce metal-binding toxicity relative to conventional hydroxamate inhibitors. <italic>In silico</italic> ADMET analysis revealed favorable physicochemical properties and predicted toxicity profiles. These computational and experimental findings provide initial rationale for further development of spiro[indoline-tetrazolo[1,5- <italic>c</italic> ]quinazoline] derivatives as selective HDAC8 inhibitors for treating HDAC8-associated disorders. </p>