Design, synthesis and biological evaluation of benzimidazole derivatives as novel human Pin1 inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 29; no. 14; pp. 1859 - 1863
• Main Authors: Ma, Tianyi, Huang, Min, Li, Aihua, Zhao, Feng, Li, Deyi, Liu, Dan, Zhao, Linxiang
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.07.2019; Elsevier
• Subjects: 4-(1H-benzoimidazol-2-yl)-benzsulfamides; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Life Sciences & Biomedicine; PC-3; Pharmacology & Pharmacy; Physical Sciences; Pin1 inhibitors; PPIase; Prostate cancer; Science & Technology; Pin1 inhibitors; 4-(1H-benzoimidazol-2-yl)-benzsulfamides; PC-3; Prostate cancer; PPIase; TARGET; PEPTIDYLPROLYL ISOMERASE; ACID; RECOGNITION; AFFINITY; PROLYL ISOMERASE PIN1; DISCOVERY
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.11.045

[Display omitted] In this work, a series of novel benzimidazole derivatives were designed and synthesized as Pin1 inhibitors. Protease-coupled assay was used to investigate the Pin1 inhibitory potency of all synthesized compounds. Thirteen of them showed preferable Pin1 inhibitory effects with IC50 values lower than 5 μM, and 12a, 15b, 15d and 16c exhibited the most promising Pin1 inhibitory activity at low micromolar level (0.33–1.00 μM) than the positive control compound Juglone. Flow cytometry results showed that treating PC-3 cells with 16c caused slight cycle arrest in a concentration-dependent manner. The structure-activity relationships of R1, R2, R3 and linker of the benzimidazole derivatives were analyzed in detail, which would help further exploration of new Pin1 inhibitors.