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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.

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