Dual targeting of neuroblastoma and cholinesterase by morpholino/ pyrrolidino-sulfonyl-indole thiosemicarbazones: Synthesis, characterization, enzyme inhibition, cytotoxicity, docking and dynamics studies

Abstract

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 IC50 values as low as 0.15 mu M and 0.12 mu M, respectively, outperforming reference drugs tacrine and galantamine. Both also showed significant cytotoxicity against SH-SY5Y neuroblastoma cells, with IC50 values of 3.8 mu M and 4.2 mu M, 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 Delta G 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 it-it 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.