Design, synthesis and biological evaluation of novel indazole-based derivatives as potent HDAC inhibitors via fragment-based virtual screening.

Based on fragment-based virtual screening and bioisoterism strategies, novel indazole and pyrazolo[3,4-b] pyridine derivatives as HDACs inhibitors were designed, synthesized and evaluated. Most of these compounds displayed good to excellent inhibitory activities against HDACs, especially compounds 15k and 15m were identified as potent inhibitors of HDAC1 (IC 50 = 2.7 nM and IC 50 = 3.1 nM), HDAC2 (IC 50 = 4.2 nM and IC 50 = 3.6 nM) and HDAC8 (IC 50 = 3.6 nM and IC 50 = 3.3 nM). Further anti-proliferation assays revealed that compounds 15k and 15m showed better anti-proliferative activities against HCT-116 and HeLa cells than positive control SAHA. The western blot analysis results indicated that compounds 15k and 15m noticeably up-regulated the level of acetylated α-tubulin and histone H3. In addition, the two compounds 15k and 15m could arrest cell cycle in G2/M phase and promote cell apoptosis, which was similar as the reference compound SAHA. Through the molecular docking and dynamic studies, the potent HDAC inhibitory activities mainly caused by van der Waals and electrostatic interactions with the HDACs. Image 1 • Representative compounds 15k and 15m exhibited potent HDAC inhibitory activities against HDAC1, 2 and 8. • 15k and 15m exhibited higher antiproliferative activities than the positive drug SAHA toward HCT-116 and HeLa. • 15k and 15m arrested cell cycle in G2/M phase and promoted cell apoptosis, which was similar as SAHA. [ABSTRACT FROM AUTHOR]