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

• Compounds with better in vitro SIRT2 inhibition than cambinol and Tenovin-6.
• Good anti-proliferative effect against three different cancer cell lines.
• Binding mode of potent compounds with SIRT2 was established.
• Novel green chemistry method in benzimidazole synthesis.
• Benzimidazoles as potential anti-cancer agent.

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.

The most active compound (4j) showed potent SIRT1 and SIRT2 inhibition with IC50 of 54.21 μM and 26.85 μM respectively. It possessed good anti-proliferative activity against three cancer cell lines tested.Figure optionsDownload as PowerPoint slide