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

Yeong Keng Yoon; Mohamed Ashraf Ali; Ang Chee Wei; Amir Nasrolahi Shirazi; Keykavous Parang; Tan Soo Choon

doi:10.1016/j.ejmech.2014.06.060

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

Eur J Med Chem. 2014 Aug 18:83:448-54. doi: 10.1016/j.ejmech.2014.06.060. Epub 2014 Jun 26.

Authors

Yeong Keng Yoon¹, Mohamed Ashraf Ali², Ang Chee Wei³, Amir Nasrolahi Shirazi⁴, Keykavous Parang⁴, Tan Soo Choon³

Affiliations

¹ Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800, Penang, Malaysia. Electronic address: kyyeong@gmail.com.
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.

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.

Keywords: Anti-proliferative; Benzimidazole; Green chemistry synthesis; Sirtuin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Benzimidazoles / chemical synthesis*
Benzimidazoles / chemistry
Benzimidazoles / metabolism
Benzimidazoles / pharmacology*
Cell Line, Tumor
Cell Survival / drug effects
Chemistry Techniques, Synthetic
Drug Design*
Green Chemistry Technology*
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / metabolism
Histone Deacetylase Inhibitors / pharmacology
Humans
Molecular Docking Simulation*
Protein Conformation
Sirtuins / antagonists & inhibitors*
Sirtuins / chemistry
Sirtuins / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
Benzimidazoles
Histone Deacetylase Inhibitors
Sirtuins