Design, synthesis, and biological screening of a series of pyrazolo [1,5-a]quina-zoline derivatives as SIRT6 activators

Elsevier

Available online 12 March 2023, 106424

European Journal of Pharmaceutical SciencesAuthor links open overlay panel, , , , , ABSTRACT

SIRT6 has emerged as a novel therapeutic target for a variety of diseases. In this study, a total of 102 pyrazolo [1,5-a]quinazoline derivatives were designed and synthesized. The result revealed that 2-methyl-N-(4-phenoxy-phenyl)pyrazolo [1,5-a]quinazoline-5-amine (21q) was the most active compound by structure-activity relationship study, which significantly enhanced SIRT6 defatty-acylation activity with an EC1.5 value of 1.85±0.41 μM and EC50 value of 11.15±0.33 μM. The biological activity of 21q was further verified by differential scanning fluorimetry assay (DSF) and surface plasmon resonance assay (SPR). Molecular docking showed that the pyrazolo [1,5-a]quinazoline of 21q formed a hydrogen bond with Val115 and four π- π interactions with Phe64, Phe82 and Phe86. 21q can significantly improve the thermal stability of SIRT6 protein and inhibit the PI3K/Akt signaling pathway in mouse embryonic fibroblasts (MEFs), thereby inhibiting the proliferation of MEFs. Collectively, we discovered a new potent SIRT6 activator, which can be taken as a lead compound for later studies.

KEYWORDS

SIRT6

defatty‐acylation

small molecule activator

Data Availability

Data will be made available on request.

© 2023 Published by Elsevier B.V.

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