Design and synthesis of novel 2-arylbenzimidazoles as selective mutant isocitrate dehydrogenase 2 R140Q inhibitors. Issue 9 (1st May 2020)

• Record Type: Journal Article
• Authors: Li, Zhenyu; Wu, Xingkang; Jia, Lejiao; Li, Jun; Zhang, Rui; Tang, Hui; Li, Zhiying; Bu, Huagang; Shen, Chengwu
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 9(2020)
• Publication Date: 2020-05-01
• Subjects: 2-Arylbenzimidazoles -- Synthesis -- IDH2 R140Q -- Inhibitors; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127070
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: The exquisite selectivity of 7c for IDH2 R140Q mutant isoform was demonstrated by the poor activity against the IDH1 R132C mutant, IDH1 R132H mutant, wild-type IDH1, IDH2 R172K mutant and the wild-type IDH2. Highlights: Synthesis of novel IDH2 R140Q inhibitors with benzimidazole scaffold via six steps reaction. Selectivity of 7c for IDH2 R140Q mutant was the best among the twenty compounds. 7c might be a lead compound deserved further structural optimization. Abstract: A series of novel 2-arylbenzimidazoles have been designed, synthesized and evaluated for their inhibitory activity against IDH2 R140Q mutant. The preliminary results indicated that four compounds 7b, 7c, 7m and 7r displayed the potent inhibitory activity against IDH2 R140Q mutant. Among them, compound 7c showed the highest inhibitory activity, with the IC50 value of 0.26 μM, which was more active than positive control enasidenib. The exquisite selectivity of 7c for IDH2 R140Q mutant isoform was demonstrated by the poor activity against the IDH1 R132C mutant, IDH1 R132H mutant, wild-type IDH1, IDH2 R172K mutant and the wild-type IDH2.