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

Abstract

A new series of thioethers containing a 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 degrees 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 min at 60 degrees C. The synthesized compounds were characterized by various spectroscopic methods (FTIR, H-1 NMR, C-13 NMR, and 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 mu M) and AChE/BChE (IC50 = 0.95 +/- 0.42 mu M/1.49 +/- 0.45 mu M) 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. The molecular docking calculations showed that molecules with high binding energy with at least one enzyme were 4b, 4d, 4g, 4h, 4i, 4j, 4k, and 4l. The physicochemical, ADMET, and drug-likeness parameters were computed using the SwissADMET online program. In silico studies of the molecules demonstrated that five molecules, 4b, 4d, 4g, 4h, and 4l, had relatively optimum drug similarity and medicinal chemistry properties. The five molecules synthesized and characterized in this study can be further investigated as drug or drug-like compound candidates.