Design, Synthesis, and Computational Studies of Novel N-(Substituted phenyl)-3-(5-((naphthalen-2-yloxy)methyl)-4-phenyl‑4H‑1,2,4-triazol-3-ylthio)acetamides as Potent Acetylcholinesterase Inhibitors.

The current studies elaborate the synthesis of some new N-(substituted phenyl)-3-(5-((naphthalen-2-yloxy)-methyl)-4-phenyl-4H-1,2,4-triazol-3-ylthio)-acetamides (8a-8h). This novel synthesis was accomplished by a well-explained protocol and structural corroboration of derivatives with the help of infrared, electron ionization mass spectrometry, and 1H nuclear magnetic resonance (NMR) and 13C NMR spectral techniques. The in vitro inhibitory potential of newly synthesized acetamides was evaluated against acetylcholinesterase enzyme, and it was explored that all the compounds showed relatively comparable potential as compared to donepezil (IC50 = 0.454 ± 0.076) used as a standard. Among the unique group of these triazoles, compound 8a depicted the maximum inhibition (IC50 = 0.697 ± 0.43). With the outcomes obtained through inhibitory investigation, it was envisaged that these compounds might serve as promising acetylcholinesterase inhibitors and might also lead to a further research gateway for getting safe and nontoxic medicinal derivatives for dealing with acetylcholinesterase-related deformities. Likewise, their bioactivity results were further validated through computational density functional theory and docking analysis to develop the structure-activity relationship finding factors responsible for variable potential through engineering structures with different chemical entities.