Batool_2025_Bioorg.Chem_167_109252

In this study, twenty novel morpholino/pyrrolidino-sulfonyl-indole thiosemicarbazone derivatives (6a-j and 7a-j) were synthesized and tested for cholinesterase inhibition and anticancer activity. Compounds 6h and 7h stood out as the most potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with IC(50) values as low as 0.15 microM and 0.12 microM, respectively, outperforming reference drugs tacrine and galantamine. Both also showed significant cytotoxicity against SH-SY5Y neuroblastoma cells, with IC(50) values of 3.8 microM and 4.2 microM, and high selectivity indices (126 for 6h and 60 for 7h) compared to normal fibroblast cells, indicating therapeutic potential. Molecular docking and MM-GBSA analyses revealed strong binding affinities with docking scores between -8.7 and - 9.3 kcal/mol and deltaG bind ranging from -55 to -62 kcal/mol. Key residues such as Trp-86, Tyr-341, Tyr-337, and Tyr-124 in AChE and Trp-82, Phe-329, Trp-231, and Pro-329 in BChE facilitated stable hydrogen bonds and Pi-Pi stacking. Molecular dynamics simulations over 250 ns confirmed complex stability with low RMSD and RMSF values. These combined results highlight 6h and 7h as promising multitarget therapeutic candidates for neurodegenerative diseases and cancer.