Design, Synthesis, and Biological Evaluation of Biphenylsulfonyl Indole‐Based Thiosemicarbazones as Potential AChE and CA I‐II Inhibitors

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ABSTRACT In this study, 20 novel biphenyl‐sulfonamide‐indole‐based thiosemicarbazone derivatives (1–20) were synthesized and evaluated for their inhibitory activities against AChE, hCA I, and hCA II. Among the synthesized compounds, compound 20 (4‐nitrophenyl substituted) exhibited the highest inhibitory activity against all three enzymes (AChE K i = 54.24 nM; hCA I K i = 12.75 nM; hCA II K i = 8.72 nM) and behaved as a competitive inhibitor in enzyme kinetic studies. To further explore the experimentally observed AChE inhibition, induced fit docking (IFD), MM‐GBSA calculations, and molecular dynamics simulations were performed for compound 20 , suggesting a plausible binding mode within the AChE active site. In silico ADME analysis indicated generally favorable drug‐like properties for the synthesized compounds. These findings identify biphenyl‐sulfonamide‐indole‐based thiosemicarbazones as promising AChE and carbonic anhydrase inhibitors for further biological investigation.