Benzimidazoles as new scaffold of sirtuin inhibitors: green synthesis, in vitro studies, molecular docking analysis and evaluation of their anti-cancer properties

Yoon YK 1 , Ali MA 2 , Wei AC 3 , Shirazi AN 4 , Parang K 4 , Choon TS 3

Affiliations 

  • 1 Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia. Electronic address: [email protected]
  • 2 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, Rajasthan 301030, India; New Drug Discovery Research, Department of Medicinal Chemistry, Sunrise University, Alwar, Rajasthan 301030, India
  • 3 Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia
  • 4 Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, United States
Eur J Med Chem, 2014 Aug 18;83:448-54.
PMID: 24992072 DOI: 10.1016/j.ejmech.2014.06.060

Abstract

Two series of novel benzimidazole derivatives were designed, synthesized and evaluated for their SIRT1 and SIRT2 inhibitory activity. Among the newly synthesized compounds, compound 4j displayed the best inhibitory activity for SIRT1 (IC50 = 54.21 μM) as well as for SIRT2 (IC50 = 26.85 μM). Cell proliferation assay showed that compound 4j possessed good antitumor activity against three different types of cancer cells derived from colon (HCT-116), breast (MDA-MB-468) and blood-leukemia (CCRF-CEM) with cell viability of 40.0%, 53.2% and 27.2% respectively at 50 μM. Docking analysis of representative compound 4j into SIRT2 indicated that the interaction with receptor was primarily due to hydrogen bonding and π-π stacking interactions.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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