Sonochemical Synthesis and In Silico Evaluation of Imidazo[1,2-a]Pyridine Derivatives as Potential Inhibitors of Sirtuins

Abstract

Encouraged by the reported sirtuin modulating ability of an imidazopyridazine derivative the structurally relevant imidazo[1,2-a]pyridine framework was explored for the design and synthesis of prospective inhibitors of sirtuins. The synthesis of targeted imidazo[1,2-a]pyridine derivatives was carried out via a NBS (N-bromosuccinimide) promoted reaction of 2-aminopyridines with β-keto esters (or 1,3-dione derivatives) in PEG-400 under ultrasound irradiation. This sonochemical method afforded the desired product in good yield when 2-aminopyridines containing electron donating methyl group were employed whereas the corresponding products were obtained in low yields when the electron withdrawing chloro group was present in 2-aminopyridines. The use of 1,3-diones in place of β-keto esters generally afforded the corresponding products in moderate to low yields. The compounds obtained from 1,3-diones were evaluated in silico against SIRT1, 2 and 3 for their potential inhibitory properties against these proteins. The carbonyl group generally played an important role in the interaction of test compounds with the target protein via formation of H-bond(s) with the appropriate residue(s). The docking studies also indicated the selective inhibition of SIRT1 over SIRT2 and 3 by the compound 4a whereas the selective SIRT3 inhibition was specified for compound 3x. Additionally, the in vitro SIRT1 inhibition e.g. 66.7 ± 2.1, 76.8 ± 1.3, 51.9 ± 3.0 and 70.1 ± 1.9% shown by 3x, 4a, 4b and 4c, respectively at 10 µM corroborated the in silico findings concerning this protein.

Graphical Abstract

A rapid and environmentally friendly sonochemical approach was developed to access imidazo[1,2-α]pyridine derivatives two of which showed promising interactions with sirtuins in silico.

Keywords:

• Imidazo[1,2-a]pyridine
• In silico study
• NBS
• PEG-400
• Sirtuin

Acknowledgements

The authors thank the management of Dr. Reddy’s Lab Ltd, Hyderabad, India, for continuous support and encouragement.

Disclosure statement

The authors confirm that this article content has no conflict of interest.

Additional information

Funding

Rambabu Dandela thanks DST-SERB for Core research grant (CRG/2018/000782).