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

作者：Iqra Naseer, Naeem Ullah, Zahra Batool, Mariya al‐Rashida, Talha Islam, Ajmal Khan, Javid Hussain, Ahmed Al-Harrasi, Zahid Shafiq, Ahmed Mohamed Tawfeek, Mohammad Shahidul Islam · 发表于：Scientific Reports · 年份：2025 · DOI：10.1038/s41598-025-24251-w · 被引用次数：2 · 研究领域：Natural Antidiabetic Agents Studies、Synthesis and biological activity、Enzyme function and inhibition

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 IC 50 values in the range 5.38–59.20 µM, vastly outperforming the reference inhibitor acarbose (IC 50 = 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.