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

• Published in: Polycyclic aromatic compounds 2023-04, Vol.43 (4), p.3741-3760
• Main Authors: Ramarao, Sidda, Pothireddy, Mohanreddy, Venkateshwarlu, Rapolu, Moturu, Krishna Murthy V. R., Siddaiah, Vidavalur, Kapavarapu, Ravikumar, Dandela, Rambabu, Pal, Manojit
• Format: Article
• Language: English
• Subjects: Carbonyl compounds; Carbonyl groups; Carbonyls; Diketones; Esters; Imidazo[1,2-a]pyridine; In silico study; Inhibitors; Irradiation; N-Bromosuccinimide; NBS; PEG-400; Proteins; Pyridines; Radiation; SIRT1 protein; Sirtuin; Sirtuins; Sonochemical reactions; Synthesis; Ultrasonic testing
• ISSN: 1040-6638; 1563-5333
• DOI: 10.1080/10406638.2022.2077774

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. 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.