Sajitha_2025_Chem.Biodivers__e202500567

A series of thiazole-piperazine sulfonamide hybrids (8a-k) were synthesized, characterized and subsequently tested on Alzheimer's disease (AD) targets, including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and the ABTS radical, to assess their effectiveness. Three of the target analogues 8c, 8e and 8g exhibited augmented inhibition on AChE with IC50 values of 2.52+/-0.92, 2.99+/-0.01 and 2.14+/-0.02 microM, respectively. These analogues also showed strong inhibition selectivity against AChE over BChE. Furthermore, the congeners 8d, 8f, 8h and 8i had remarkable ABTS radical scavenging properties as their IC50 values were in the range of 0.05+/-0.07 to 0.99+/-0.12 microM. A study of the kinetics of inhibition of AChE for active analogue 8g revealed a mixed type of inhibition. From the molecular docking experiments, it was clear that the compounds 8c, 8e and 8g were placed optimally within the active site of AChE. Molecular dynamics (MD) simulations of these docked complexes indicated that the root mean square deviation (RMSD) of the complexes stabilized below 4 A. Furthermore, in silico ADMET prediction studies revealed that the targeted analogs satisfied all the characteristics of CNS acting drugs. Finally, these active compounds are determined to be non-toxic and highly neuroprotective against H2O2-induced cell death in SK-N-SH cell lines.