Inhibition of Acetylcholinesterase with Novel 1, 3, 4, Oxadiazole Derivatives: A Kinetic, In Silico, and In Vitro Approach

Alzheimer's disease (AD) is a neurological disease that disturbs the memory, thinking skills, and behavior of the affected person. AD is a complex disease caused by the breakdown of acetylcholine via acetylcholinesterase (AChE). The present study aimed to assess the synthetic inhibitors of AChE that could be used to treat AD. For this purpose, synthetic compounds of oxadiazole derivatives (15-35) were evaluated and identified as promising inhibitors of AChE, exhibiting IC₅₀ varying between 41.87 ± 0.67 and 1580.25 ± 0.7 μM. The kinetic parameters indicated that all the studied compounds bind to the allosteric site and decrease the efficiency of the AChE enzyme. In silico docking analysis showed that the majority of the compounds interact with the anionic subsite and Per-Arnt-Sim domain of AChE and are stabilized by various bonds including π-π and hydrogen bonding. The stability of the most potent compounds 16 and 17 with AChE interaction was confirmed by molecular dynamics simulations. Moreover, all compounds exhibited concentration-dependent calcium (Ca²⁺) antagonistic and spasmolytic activities. Among the whole series of oxadiazole derivatives, compounds 16 and 17 displayed the highest activities on spontaneous and potassium (K⁺)-induced contraction. Therefore, the AChE inhibitory potential, cytotoxicity safe profile, and Ca²⁺ antagonistic ability of these compounds make them potential therapeutic agents against AD and its associated problems in the future.