Design, Synthesis and Biological Evaluation of 5-Alkyl[1,2,4]triazino [5,6-b]indole-3-thiol Based Compounds as Potential Histone Deacetylase Inhibitor Candidates

The resilient nature of cancer limits the long-term efficacy of conventional single-target chemotherapeutics, motivating the development of structurally novel anticancer agents with potential multitarget activity. This study aimed to design, synthesize, and biologically and computationally evaluate a new series of triazinoindole-capped acid-hydrazide hybrids designed to interact with histone deacetylases. Twelve novel compounds (6a–l) were synthesized and characterized. Their antiproliferative activity was evaluated against HCT-116, MCF-7, and HepG2 cell lines, while their potential interactions with HDAC4, HDAC6, and HDAC8 were investigated using molecular docking and induced-fit docking. Drug-likeness and in silico ADMET properties were also evaluated to assess their preliminary developability. N-Ethylation combined with one-, three-, and four-carbon linkers was associated with broader antiproliferative activity. Compound 6j was the most active analog, with IC50 values ranging from 2 to 7 µM. Docking and induced-fit docking analyses suggested favorable binding interactions within the investigated binding sites, supporting the potential involvement of HDACs in the biological activity of these compounds. ADMET profiling indicated full compliance with Lipinski’s rule of five across the series. Overall, the findings identify the triazinoindole–acid-hydrazide scaffold as a structurally tunable and promising anticancer chemotype with computationally supported HDAC-targeting potential, with compound 6j emerging as a potential candidate for further investigation.