Synthesis, in vitro, and in silico studies of 4-chlorophenyl-sulfonyl Indole based thiosemicarbazones as competitive α-glucosidase inhibitors

The urgent need for effective and novel solutions to address the rising global epidemic of diabetes mellitus (DM) has become a priority for researchers. This chronic ailment, with its alarming prevalence and life-threatening complications (neuropathy, retinopathy and nephropathy), necessitates novel therapeutic strategies. Herein we have synthesized a novel series of N-substituted indole-based thiosemicarbazone derivatives 5(a-y) and explored their potential as α-glucosidase inhibitors. All the compounds displayed excellent inhibitory potential with IC₅₀ values in the range 5.38-59.20 µM, vastly outperforming the reference inhibitor acarbose (IC₅₀ = 871.40 ± 1.24 µM). Molecular docking and molecular dynamics simulation were also conducted, which revealed strong binding interactions with the active site of the enzyme. Compound 5u emerged as the most effective α-glucosidase inhibitor, making it a strong lead for the development of novel antidiabetic therapeutics. To strengthen the SAR rationale and to gain mechanistic insights into the enhanced α-glucosidase inhibition, quantum chemical descriptors of the eight most active thiosemicarbazones (5a, 5 h, 5 m, 5n, 5s, 5t, 5u, 5w) were computed using DFT, highlighting their reactivity and stability from a theoretical perspective.