Novel Lawsone-Quinoxaline Hybrids as New Dual Binding Site Acetylcholinesterase Inhibitors

Paptawan Suwanhom; Teerapat Nualnoi; Pasarat Khongkow; Varomyalin Tipmanee; Luelak Lomlim

doi:10.1021/acsomega.3c02683

Novel Lawsone-Quinoxaline Hybrids as New Dual Binding Site Acetylcholinesterase Inhibitors

ACS Omega. 2023 Aug 29;8(36):32498-32511. doi: 10.1021/acsomega.3c02683. eCollection 2023 Sep 12.

Authors

Paptawan Suwanhom^{1

2}, Teerapat Nualnoi³, Pasarat Khongkow⁴, Varomyalin Tipmanee⁴, Luelak Lomlim^{1

2}

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand.
² Phytomedicine and Pharmaceutical Biotechnology Excellent Center (PPBEC), Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand.
³ Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand.
⁴ Department of Biomedical Sciences and Biomedical Engineering, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand.

Abstract

A new family of lawsone-quinoxaline hybrids was designed, synthesized, and evaluated as dual binding site cholinesterase inhibitors (ChEIs). In vitro tests revealed that compound 6d was the most potent AChEI (IC₅₀ = 20 nM) and BChEI (IC₅₀ = 220 nM). The compound 6d did not show cytotoxicity against the SH-SY5Y neuronal cells (GI₅₀ > 100 μM). In silico and enzyme kinetic experiments demonstrated that compound 6d bound to both the catalytic anionic site and the peripheral anionic site of HuAChE. The lawsone-quinoxaline hybrids exhibited potential for further development of potent acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.