Background: Histone deacetylases (HDAC) enzymes are emerging as potential targets
for cancer treatments. In this study, several series of novel hydroxamic acids incorporating 1-((1H-
1,2,3-triazol-4-yl)methyl)-3-substituted-2-oxoindolines were explored.
Methods: The compounds were designed using Autodock Vina program, then synthesized and
evaluated in vitro and in silico for their inhibitory activity against HDACs. The cytotoxicity was
measured by SRB method. The enzyme inhibitory effects of the compounds were evaluated by the
Results: Biological evaluation showed that these hydroxamic acids were generally cytotoxic
against four human cancer cell lines (SW620, colon; PC-3, prostate; AsPC-1, pancreas; NCI-H23,
lung). Several compounds, e.g. 7g, 11c, and 11g, displayed up to 10-fold more potent than SAHA
(suberoylanilide hydroxamic acid, vorinostat) in term of cytotoxicity. The synthesized compounds
were also comparably potent to SAHA in inhibiting HDAC2. In particular, compound 11c displayed
potential inhibitory effects against HDAC1, HDAC2, HDAC6, and HDAC8 with comparable
or slightly higher potency than SAHA. Docking results on four class I and IIB isoenzymes indicated
that these compounds tightly bound to HDACs at the active site with binding affinities
much higher than that of SAHA. Finally, chemo-informatics approaches were employed to assess
the pharmacokinetic and toxicity profiles of 7g and 11c. We identified degradation via phase II
metabolism and toxicity two of the most serious problems that need further optimization.
Conclusion: Taking altogether our findings are encouraging and current hydroxamate derivatives
are worth being considered as potential HDAC inhibitors and could be useful for further research
on the development of new anti-cancer agents.