Design, synthesis and biological evaluation of new 1,ω-Bis-(5-alkyl-3-tosyl-1,3,4,2-triazaphospholino)alkanes as in vitro α-amylase and lipase inhibitors

Abstract

A series of new 1,ω-bis-(5-alkyl-3-tosyl-1,3,4,2-triazaphospholino)alkanes 2 and 3 were obtained in excellent yields by the condensation of 1,ω-bis-(1-tosylamidrazone)alkanes 1 with two equivalent molars of Lawesson's Reagent (LR) and trisdimethylaminophosphine, respectively. All synthesized compounds were characterized by various spectroscopic techniques including IR, ¹H NMR, ¹³C NMR and ³¹P NMR and elemental analysis. The newly synthesized compounds were evaluated against key enzymes related to diabetes and obesity such as α-amylase and lipase. This study showed that the compounds 3a and 2b are an excellent inhibitor of α-amylase (with IC₅₀ = 18.8 mM) and lipase (with IC₅₀ = 19 mM) respectively, as compared with standard, orlistat (IC₅₀ = 22 mM). Among this series, compounds 3a and 2b with the CH₃ or C₂H₅ group at position 6 were identified as the most potent inhibitors against α-amylase, and lipase enzymes. The remaining compounds were found to be moderately active. Further, molecular docking simulation studies were done to identify the interactions and binding mode of synthesized analogs at binding site of α-amylase and lipase enzymes.

Keywords: 1,ω-bis(1-tosylamidrazone)alkanes; 1,ω-bis(5-alkyl-3-tosyl-1,3,4,2-triazaphospholine-2-oxide)alkanes; Diabetes; Lawesson's reagent; Obesity; Trisdimethylaminophosphine.