Synthesis and inhibitory activity against enzymes responsible for Type 2 diabetes mellitus of lactose-conjugated thiosemicarbazones from substituted acetophenones

Abstract

An acetophenone thiosemicarbazone series 6a-m containing lactose moiety were synthesized and explored for their inhibition against the enzymes responsible in Type 2 diabetes mellitus (T2DM), including α-amylase, α-glucosidase, DPP-4, and PTP1B. Two thiosemicarbazones exhibited the highest inhibitory activity against these enzymes, 6i against α-glucosidase (IC₅₀ = 7.15 ± 0.12 μM) and 6m against α-amylase, DPP-4, and PTP1B (with IC₅₀ = 7.82 ± 0.14 µM, 1.32 ± 0.02 µM, and 3.74 ± 0.14 μM when compared to the corresponding standard drugs). These compounds also exhibited the high anti-glycation and antioxidant activity in DPPH and ABTS^•+ scavenging assays. They were noncytotoxic for WI-38 cell line with IC₅₀ >85 μM. Molecular docking study applied to these two most potential inhibitors on enzymes, including 3TOP for inhibitor 6i, 1OSE, 3W2T, and 1NNY for inhibitor 6m. These ligands had active interactions with the residues in the catalytic pocket of these corresponding enzymes that was consistent with their obtained inhibitory efficacy against each enzyme tested. The 300 ns molecular dynamics simulations applied for the complexes, including 6m/1OSE, 6i/3TOP, 6m/3W2T, and 6m/1NNY, to validate the obtained in vitro biological activity data of these inhibitors. The obtained results indicated that these inhibitors had stable dynamic interactions in the catalytic pockets of the respective enzymes to promote their activity.