title: Synthesis and evaluation of novel benzimidazole derivatives as sirtuin inhibitors with antitumor activities.
abstract: A total of 15 novel benzimidazole derivatives were designed, synthesized and evaluated for their SIRT1 and SIRT2 inhibitory activity. All compounds showed better inhibition on SIRT2 as compared to SIRT1. Among these, compound 5j displayed the best inhibitory activity for SIRT1 (IC50=58.43μM) as well as for SIRT2 (IC50=45.12μM). Cell cytotoxicity assays also showed that compound 5j possesses good antitumor activity against two different cancer cell lines derived from breast cancer (MCF-7 and MDA-MB-468). A simple structure-activity-relationship (SAR) study of the newly synthesized benzimidazole derivatives was also discussed.
authors.affiliation: Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia. Electronic address: kyyeong@gmail.com.
authors.forename: Yeong Keng
authors.initials: YK
authors.lastname: Yoon
authors.affiliation: Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia; New Drug Discovery Research, Department of Medicinal Chemistry, Alwar Pharmacy College, Alwar 301030, Rajasthan, India; New Drug Discovery Research, Department of Medicinal Chemistry, Sunrise University, Alwar 301030, Rajasthan, India.
authors.forename: Mohamed Ashraf
authors.initials: MA
authors.lastname: Ali
authors.affiliation: Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
authors.forename: Ang Chee
authors.initials: AC
authors.lastname: Wei
authors.affiliation: Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
authors.forename: Tan Soo
authors.initials: TS
authors.lastname: Choon
authors.affiliation: School of Chemical Sciences, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia.
authors.forename: Hasnah
authors.initials: H
authors.lastname: Osman
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, United States.
authors.forename: Keykavous
authors.initials: K
authors.lastname: Parang
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, United States.
authors.forename: Amir Nasrolahi
authors.initials: AN
authors.lastname: Shirazi
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D061986:MCF-7 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; C031000:benzimidazole; C447939:SIRT1 protein, human; C474199:SIRT2 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2
keywords: Anti-proliferative; Benzimidazole; Breast cancer; Electron donating; Sirtuin