3-(7-Azaindolyl)-4-indolylmaleimides as a novel class of mutant isocitrate dehydrogenase-1 inhibitors: Design, synthesis, and biological evaluation.

A series of 3-(7-azainodyl)-4-indolylmaleimides was designed, synthesized, and evaluated for their isocitrate dehydrogenase 1 (IDH1)/R132H inhibitory activities. Many compounds such as 11a, 11c, 11e, 11g, and 11s exhibited favorable inhibitory effects on IDH1/R132H and were highly selective against the wild-type IDH1. Evaluation of the biological activities at the cellular level showed that compounds 11a, 11c, 11e, 11g, and 11s could effectively suppress the production of 2-hydroxyglutaric acid in U87MG cells expressing IDH1/R132H. Preliminary structure-activity relationship (SAR) and molecular modeling studies were discussed based on the experimental data obtained. These findings may provide new insights into the development of novel IDH1/R132H inhibitors.