Tariq_2022_Chem.Biodivers__

A sequence of 1,3,4-oxadiazole 2-thiol derivatives bearing various alkyl or aryl moieties was designed, synthesized, and characterized by modern spectroscopic methods to yield 17 compounds ( 6a - 6q ) which were screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes in search of 'lead' compounds for the treatment of Alzheimer disease (AD). The compounds 6q, 6p, 6k, 6o, and 6l showed inhibitory capability against AChE and BChE, with IC 50 values ranging from 11.730.49 to 27.360.29 microM for AChE and 21.830.39 to 39.430.44 microM for BChE, inhibiting both enzymes within a limited range. The SAR ascertained that the substitution of the aromatic moiety had a profound effect on the AChE and BChE inhibitory potential as compared to the aliphatic substitutions which were supported by the molecular docking studies. In silico ADME studies reinforced the drug-likeness of most of the synthesized molecules. These results were additionally supplemented by the molecular orbital analysis (HOMO-LUMO) and electrostatic potential maps got from DFT calculations. ESP maps expose that on all structures, there are two potential binding sites conquered by the most positive and most negative districts.