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

Eur J Pharm Sci. 2023 Jun 1:185:106424. doi: 10.1016/j.ejps.2023.106424. Epub 2023 Mar 12.

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: Defatty‐acylation; SIRT6; Small molecule activator.

MeSH terms

  • Animals
  • Fibroblasts / metabolism
  • Mice
  • Molecular Docking Simulation
  • Molecular Structure
  • Phosphatidylinositol 3-Kinases / metabolism
  • Pyrazoles* / chemistry
  • Pyrazoles* / pharmacology
  • Quinazolines* / chemistry
  • Quinazolines* / pharmacology
  • Sirtuins* / drug effects
  • Sirtuins* / metabolism
  • Structure-Activity Relationship

Substances

  • Phosphatidylinositol 3-Kinases
  • Quinazolines
  • Sirt6 protein, mouse
  • Sirtuins
  • Pyrazoles