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

Maria Ayub; Sabahat Zahra Siddiqui; Aziz-Ur Rehman; Muhammad Athar Abbasi; Riffat Parveen; Syed Adnan Ali Shah; Aamir Mushtaq; Javed Iqbal; Hira Khalid; Syahrul Imran; Ghazanfar Abbas

doi:10.1021/acsomega.5c04448

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

ACS Omega. 2025 Sep 29;10(39):45191-45203. doi: 10.1021/acsomega.5c04448. eCollection 2025 Oct 7.

Authors

Affiliations

¹ Department of Chemistry, Institute of Chemical Sciences, Government College University, Lahore 54000, Pakistan.
² Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan.
³ Faculty of Pharmacy, Universiti Teknologi MARA Cawangan Selangor Kampus Puncak Alam, Bandar Puncak Alam-42300, Shah Alam, Selangor 40450, Malaysia.
⁴ Atta-ur-Rahman Institute for Natural Product Discovery (AuRIns), Universiti Teknologi MARA Cawangan Selangor Kampus Puncak Alam, Bandar Puncak Alam, Selangor 42300, Malaysia.
⁵ Department of Pharmaceutical Sciences, Institute of Chemical Sciences, Government College University, Lahore 54000, Pakistan.
⁶ Department of Chemistry, University of Sahiwal, Sahiwal 57000, Pakistan.
⁷ Department of Chemistry, Forman Christian College University, Lahore 54600, Pakistan.

Abstract

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.