Novel Hydroxamic Acids Incorporating 1-((1 H -1,2,3-triazol-4-yl)methyl)-3-hydroxyimino-indolin-2-ones: Synthesis, Biological Evaluation, and SAR Analysis

A series of seventeen novel hydroxamic acids incorporating 1-((1H-1,2,3-triazol-4-yl)methyl)-3-hydroxyimino-indolin-2-ones was designed and synthesized. Biological evaluation showed that these hydroxamic acids potently inhibited a class-I isoform of HDACs (HDAC2) with \(\hbox {IC}_{50}\) values in low micromolar range. Several compounds also exhibited good cytotoxicity. Two compounds, 5e and 5f, emerged as the most potent HDAC2 inhibitors with cytotoxicity up to 8-fold more potent than SAHA in three human cancer cell lines, including SW620 (colon cancer), PC3 (prostate cancer) and AsPC-1 (pancreatic cancer). A molecular modeling approach has been carried out which revealed some structure-activity relationships. Further investigation on absorption, distribution, metabolism, excretion and toxicity (ADMET) suggested that compounds 5e and 5f, while showing potent HDAC2 inhibitory bioactivity, hold desirable characteristics for anticancer compounds.