An expedient, ionic liquid mediated multi-component synthesis of novel piperidone grafted cholinesterase enzymes inhibitors and their molecular modeling study

•Novel piperidone-grafted pyrimidines synthesized in good yield.•Green multi-component ionic liquid mediated methodology was utilized.•Compounds 6a, 6h and 6i showed higher AChE inhibitory activities comparing standard.•All the compounds displayed better BChE inhibitory activities contrasting standard.•Molecular modeling simulation completely coincided with in vitro inhibitory results.

Series of hitherto unreported piperidone grafted pyridopyrimidines synthesized through ionic liquid mediated multi-component reaction. These compounds were evaluated for their inhibitory activities against AChE and BChE enzymes. All the compounds displayed considerable potency against AChE with IC50 values ranging from 0.92 to 9.11 μM, therein compounds 6a, 6h and 6i displayed superior enzyme inhibitory activities compared to standard drug with IC50 values of 0.92, 1.29 and 2.07 μM. Remarkably, all the compounds displayed higher BChE inhibitory activity compared to galantamine with IC50 values of 1.89–8.13 μM. Molecular modeling, performed for the most active compounds using three dimensional crystal structures of TcAChE and hBChE, disclosed binding template of these inhibitors into the active site of their respective enzymes.

Graphical abstractNovel pyridopyrimidines synthesized and evaluated for cholinesterase enzymes inhibitory activity. All the compounds displayed considerable potency against AChE and BChE with IC50 values ranging from 0.92 to 9.11 μM.Figure optionsDownload full-size imageDownload as PowerPoint slide