Exploration of dual fatty acid amide hydrolase and cholinesterase inhibitory potential of some 3-hydroxy-3-phenacyloxindole analogs

Abstract

The dual inhibition of fatty acid amide hydrolase (FAAH) and cholinesterases (ChEs) has recently egressed as a novel strategy for the management of neurodegeneration. In the present work, a library of 3-hydroxy-3-phenacyloxindole analogs was screened for FAAH and ChEs (acetylcholinesterase [AChE]/butyrylcholinesterase [BuChE]) inhibition. 1-Benzyl-3-hydroxy-3-(2′,4′-dibromophenacyl)oxindole (16), the most promising compound, showed a balanced multifunctional profile with FAAH (IC50 = 8.7 ± 0.3 nM, competitive and reversible), AChE (IC50 = 28 ± 3 nM, mixed and reversible), and BuChE (IC50 = 65 ± 8 nM, mixed and reversible) inhibition. The structure–activity relationship study predicted multifarious fundamental aspects crucial for the potency of these analogs. Furthermore, the structural geometry and rigidness bestowed by the oxindole moiety resulted in improved adherence of the compounds within the binding pockets of the target enzymes. Molecular docking studies of the docked conformations acknowledged numerous interactions for trenchant stabilization of inhibitor–enzyme complexes. Binding interaction and conformational alignment studies of stereoisomers of the lead inhibitors highlighted the importance of the (S)-stereochemistry at C-3 of the oxindole scaffold for potency and selectivity. Compound 16 also displayed an antioxidant potential surpassing that of ascorbic acid, and it was non-neurotoxic. In silico molecular and ADMET properties anticipated druglikeness of the test compounds for oral use. Thus, compound 16 emerged as a new and interesting multifaceted candidate that could further be explored for its potential multitargeted role in the discovery of drugs for the treatment of Alzheimer's disease. © 2020 Deutsche Pharmazeutische Gesellschaft