Synthesis, enzyme inhibition and molecular docking studies of novel 1,2,4-oxadiazole thioether derivatives

Abstract A new series of thioethers containing 1,2,4-oxadiazole ring were synthesized by the modified Riemschneider Reaction. The corresponding thiocyanate derivatives of 1,2,4-oxadiazoles were obtained in good yields by the reaction of 3-aryl-5-chloromethyl-1,2,4-oxadiazole compounds with NH4SCN in triethylene glycol at 60 °C as a new method. Thioether derivatives were synthesized by reacting 5-thiocyanato-3-aryl-1,2,4-oxadiazole with various tertiary or secondary alcohols in solvent-free conditions for 10-30 minutes at 60 °C. The synthesized compounds were characterized by various spectroscopic methods (FTIR, 1H NMR, 13C NMR, HRMS). All 1,2,4-oxadiazole-thioethers were tested for xanthine oxidase (XO), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibition potential. The results showed that 4 h has more potential inhibition activity than positive control for XO (IC50= 0.41 ± 0.067 µM) and AChE/BChE (IC50= 0.95 ± 0.42 µM / 1.49 ± 0.45 µM) and is considerably greater than other compounds. Moreover, our experimental study was supported by molecular docking to describe the binding mode of new structures to enzymes.