Issue 7, 2022

Design and synthesis of amino acid derivatives of substituted benzimidazoles and pyrazoles as Sirt1 inhibitors

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.

Graphical abstract: Design and synthesis of amino acid derivatives of substituted benzimidazoles and pyrazoles as Sirt1 inhibitors

Supplementary files

Article information

Article type
Paper
Submitted
14 août 2021
Accepted
10 janv. 2022
First published
30 janv. 2022
This article is Open Access
Creative Commons BY-NC license

RSC Adv., 2022,12, 3809-3827

Design and synthesis of amino acid derivatives of substituted benzimidazoles and pyrazoles as Sirt1 inhibitors

N. Purushotham, M. Singh, B. Paramesha, V. Kumar, S. Wakode, S. K. Banerjee, B. Poojary and S. Asthana, RSC Adv., 2022, 12, 3809 DOI: 10.1039/D1RA06149F

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