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

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 Ki = 54.24 nM; hCA I Ki = 12.75 nM; hCA II Ki = 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.