Synthesis and Enzyme Inhibitory Evaluation of Fluoro-Substituted 1,3,4-Oxadiazoles: Dual Inhibitors of Urease and Glucosidase with Insightful Structure-Activity Relationships

초록

The synthesis of a series of new fluorophenyl- and alkyl-substituted 1,3,4-oxadiazole derivatives (4a-o), which act as potent enzyme inhibitors selectively targeting urease and alpha-glucosidase, is reported in this study. These compounds were prepared via a multi-step process involving the cyclization of thiosemicarbazides, derived from alkyl hydrazides and fluorophenyl isothiocyanates, with the hydrazides prepared from aliphatic esters. FT-IR, NMR, and EI-MS studies were used to assess the structures of the synthesized 1,3,4-oxadiazoles. Enzyme inhibitory assay exhibited that 4-fluorophenyl-substituted 1,3,4-oxadiazoles with butyl (4k), hexyl (4l), heptyl (4m), and nonyl (4n) side chains exhibited significant urease inhibition, with half-maximal inhibitory concentration (EC50) values of 48.58 +/- 3.2, 57.51 +/- 0.1, 68.60 +/- 0.1, and 88.76 +/- 0.2 mu M, respectively, compared to the standard thiourea (EC50 24.14 mu M). Additionally, compounds 4k, 4l, and 4m demonstrated promising alpha-glucosidase inhibition, with EC50 values of 136.04 +/- 0.3, 153.45 +/- 1.9, and 194.66 +/- 1.7 mu M, respectively, relative to the standard acarbose (EC50 51.23 mu M). Moreover, molecular docking studies highlighted critical binding interactions, with compounds 4k and 4l exhibiting the strongest docking affinities, correlating well with their in vitro inhibition results, while 4m also demonstrated significant binding interactions despite its higher EC50, offering deeper insights into structure-activity relationships.

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