Towards the discovery of potent epigenetic modulators: Design, synthesis, biological evaluation, and SAR investigation of novel indole-based derivatives targeting HDAC1 and HDAC6.

Histone deacetylases (HDACs) serve as crucial epigenetic modulators implicated in tumorigenesis. Consequently, targeting HDACs is considered an emerging strategy in cancer therapy. Leveraging scaffold hopping and structural optimization strategies, we developed fifteen indole-based derivatives utilizing vorinostat (SAHA) and entinostat as lead compounds. The synthesized compounds were evaluated against HDAC1 and HDAC6 isoforms, revealing that all the hydroxamate derivatives (15a-c, 16a, 16b, 17, and 18) displayed potent HDAC1/6 inhibitory activity with preferential inhibition of HDAC6, exhibiting IC50 values in the low nanomolar range (1-12 nM) against HDAC6, surpassing SAHA by 2- to 16-fold. In contrast, the benzamide derivatives (23a-c, 24, 25, and 26) exhibited notable preferential inhibition of HDAC1 over HDAC6. Furthermore, HDAC isoform selectivity profiling revealed that 18 preferentially inhibited HDAC6 over class I isoforms, whereas 23c showed a preference for HDAC1 inhibition. Comparative molecular docking of 18 and SAHA provided supportive insight consistent with the observed higher potency of 18. Intriguingly, the preliminary screening against the NCI-60 panel at 10 μM indicated ten compounds with pronounced antiproliferative activity, warranting their progression to subsequent concentration-response screening. Notably, the benzamide series exhibited potent cytotoxicity with GI50 values in the nanomolar to low micromolar range across the entire NCI-60 panel. Mechanistic investigations of representative hydroxamate and benzamide derivatives corroborated their marked antiproliferative effects in HCT-116 cancer cells and manifested a favorable safety profile against the normal fibroblasts (WI-38). Altogether, these findings underscore the therapeutic potential of the identified potent compounds for combating cancer via HDAC1/6 inhibition.