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

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 beta-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 beta-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 mu M corroborated the in silico findings concerning this protein.