Design, synthesis, in vitro acetylcholinesterase, butyrylcholinesterase activities, and in silico molecular docking study of oxindole-oxadiazole hybrid analogues

Alzheimer's disease is a neurological disorder characterized by cognitive dysfunction and deficits in activities of daily living. There is no drug available for Alzheimer's at the moment, and the inhibition of acetylcholinesterase and butyrylcholinesterase enzymes are a good target to treat Alzheimer's disease. In this study, a series of new oxindole-oxadiazole hybrid analogues (1-18) have been synthesized and evaluated for acetylcholinesterase and butyrylcholinesterase inhibitory activities. All compounds showed a varied degree of inhibition, ranging from 0.80 +/- 0.20 to 12.50 +/- 0.40 mu M (against acetylcholinesterase) and 1.10 +/- 0.20 to 20.30 +/- 0.10 mu M (against butyrylcholinesterase), as compared to the standard inhibitor donepezil (IC50 values of 2.16 +/- 0.12 & 4.5 +/- 0.11 mu M, respectively). In the case of acetylcholinesterase, analogue 17 (IC50 = 0.80 +/- 0.20 mu M) while in case of butyrylcholinesterase, analogue 5 (IC50 = 1.10 +/- 0.20 mu M) was found the most potent among the whole series. Structure-activity relationship has been established for all compounds, which mainly depended upon the nature, number, position, and electron-donating or-withdrawing effect of the substituent(s) on the phenyl ring. A molecular docking study was carried out to investigate the interaction of the most potent compounds with the active site of enzymes. The stability of each drug-like hit in complex with acetylcholinesterase and butyrylcholinesterase was determined by computing their RMSD, RMSF analysis. Among all the compounds, compound 17 and compound 5 respectively, revealed a good interactions and stability during the entire simulation procedure.