Novel Thiadiazole Derivatives as Potential Anti‐Alzheimer Agent: Synthesis, Activity of Molecular Interactions and their in Silico Assessment

Abstract A series of thiadiazole derivatives were designed and synthesized as dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) for the treatment of Alzheimer's disease (AD). Furthermore, the compounds were assayed for their inhibitory activity to AChE and BuChE in vitro , and the results indicated that most of the compounds had moderate inhibitory activity to AChE and BuChE. Among them, compound 11 u showed the best inhibitory activity against AChE and BuChE (eeAChE, IC 50 =2.73 μM; eqBuChE, IC 50 =0.65 μM), which showed approximately 2‐fold more activity against AChE enzyme than galantamine and approximately 28‐fold more activity against BuChE enzyme than galantamine. In addition, molecular docking studies have shown that compound 11 u could bind to the catalytic active site (CAS) and peripheral anion site (PAS) of AChE and BuChE. Among them, compound 11 u combined with BuChE and exhibited a mixed inhibition pattern consistent with enzyme kinetics studies. The interaction's stability of 11 u ‐AChE/BuChE were also assessed using a conventional atomistic 100 ns dynamics simulation study, which revealed the conformational stability of representative compound 11 u in the cavity of the AChE/BuChE. Moreover, the molecular properties of all compounds were predicted by online through the SwissADME, and the best active compound 11 u matched the properties of most orally administered drugs. All these suggested that 11 u could be considered as a lead compound for the development of drugs for AD.