Design, Synthesis, Characterization and In Vitro Evaluation of Anticholinesterase and Antioxidant Activities of Thiazole–Piperazine Sulphonamide Hybrids

ABSTRACT A series of thiazole–piperazine sulphonamide 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 IC 50 values of 2.52 ± 0.92, 2.99 ± 0.01 and 2.14 ± 0.02 µM, 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 IC 50 values were in the range of 0.05 ± 0.07–0.99 ± 0.12 µM. 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 by interacting with both the catalytic active site (CAS) and the peripheral anionic site (PAS) and served as evidence for mixed type of inhibition. Molecular dynamics (MD) simulations of these docked complexes indicated that the root‐mean‐square deviation (RMSD) of the complexes stabilized below 4 Å. Among the ligands, 8c exhibited the highest stability, with an RMSD of 3.0 ± 0.30 Å, compared to 8e (3.77 ± 0.38 Å) and 8g (3.50 ± 0.52 Å) in complex with human AChE (hAChE). Furthermore, in silico ADMET prediction studies revealed that the targeted analogues satisfied all the characteristics of central nervous system (CNS) acting drugs. Finally, these active compounds are determined to be nontoxic and highly neuroprotective against H 2 O 2 ‐induced cell death in SK‐N‐SH cell lines. These results inferred that the thiazole–piperazine sulphonamide derivatives have the potential to serve as a valuable molecular template for further in vitro and in vivo assessments in the context of the development of anti‐AD agents.