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

The current studies elaborate the synthesis of some new <i>N-</i>(substituted phenyl)-3-(5-((naphthalen-2-yloxy)-methyl)-4-phenyl-4<i>H</i>-1,2,4-triazol-3-ylthio)-acetamides (<b>8a</b>-<b>8h</b>). 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 <i>in</i> <i>vitro</i> 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 <b>8a</b> 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.