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Design and synthesis of amino acid derivatives of substituted benzimidazoles and pyrazoles as Sirt1 inhibitors
Authors:Nikil Purushotham  Mrityunjay Singh  Bugga Paramesha  Vasantha Kumar  Sharad Wakode  Sanjay K. Banerjee  Boja Poojary  Shailendra Asthana
Affiliation:Department of Studies in Chemistry, Mangalore University, Mangalagangotri Karnataka-574 199 India, +91 9686940403 ; Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, Faridabad Haryana-121001 India, +91 1292876475, +91 1292876489, +91 8447568689 ; Delhi Institute of Pharmaceutical Sciences and Research, DPSR University, M.B Road, Pushp Vihar, Sector 3, New Delhi 110017 India
Abstract:
Owing to its presence in several biological processes, Sirt1 acts as a potential therapeutic target for many diseases. Here, we report the structure-based designing and synthesis of two distinct series of novel Sirt1 inhibitors, benzimidazole mono-peptides and amino-acid derived 5-pyrazolyl methylidene rhodanine carboxylic acid. The compounds were evaluated for in vitro enzyme-based and cell-based Sirt1 inhibition assay, and cytotoxic-activity in both liver and breast cancer cells. The tryptophan conjugates i.e.13h (IC50 = 0.66 μM, ΔGbind = −1.1 kcal mol−1) and 7d (IC50 = 0.77 μM, ΔGbind = −4.4 kcal mol−1) demonstrated the maximum efficacy to inhibit Sirt1. The MD simulation unveiled that electrostatic complementarity at the substrate-binding-site through a novel motif “SLxVxP(V/F)A” could be a cause of increased Sirt1 inhibition by 13h and 13l over Sirt2 in cell-based assay, as compared to the control Ex527 and 7d. Finally, this study highlights novel molecules 7d and 13h, along with a new key hot-spot in Sirt1, which could be used as a starting lead to design more potent and selective sirtuin inhibitors as a potential anticancer molecule.

Owing to its presence in several biological processes, Sirt1 acts as a potential therapeutic target for many diseases.
Keywords:
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