Synthesis and docking calculations of tetrafluoronaphthalene derivatives and their inhibition profiles against some metabolic enzymes

Abstract

Syntheses of tetrahydroepoxy, O‐allylic, O‐prenylic, and O‐propargylic tetrafluoronaphthalene derivatives, starting from 1‐bromo‐2,3,4,5,6‐pentafluorobenzene, are reported here for the first time. The O‐substituted tetrafluoronaphthalene derivatives were designed and also synthesized via a one‐pot nucleophilic substitution reaction in excellent yields, whereas the tetrafluorotetrahydroepoxynaphthalene derivate was synthesized via a reduction reaction in excellent yield. The chemical structures of all the synthesized molecules were characterized by nuclear magnetic resonance, infrared spectroscopy, and high‐resolution mass spectrometry techniques. In this study, a series of novel tetrafluoronaphthalene derivatives (2, 2a, 4–6) was tested toward several enzymes including α‐glucosidase, acetylcholinesterase (AChE), and human carbonic anhydrase I and II (hCA I/II). The tetrafluoronaphthalene derivatives 2, 2a, and 4–6 showed IC50 and Ki values in the range of 0.83–1.27 and 0.71–1.09 nM against hCA I, 1.26–1.85 and 1.45–5.31 nM against hCA II, 39.02–56.01 and 20.53–56.76 nM against AChE, and 15.27–34.12 and 22.58–30.45 nM against α‐glucosidase, respectively. Molecular docking calculations were made to determine the biological activity values of the tetrafluoronaphthalene derivatives against the enzymes. After the calculations, ADME/T analysis was performed to examine the effects on human metabolism. Finally, these compounds had antidiabetic and anticholinesterase potentials.