Multifunctional anti-Alzheimer's agents: Synthesis, biological evaluation, and molecular docking study of new 2-phenoxyacetamide/3-phenoxypropanamide/4-oxobutanamide derivatives


Shakila S., KILIÇ B., Bardakkaya M., Aksakal F., Sagkan R. I., DOĞRUER D. S.

Journal of Molecular Structure, vol.1317, 2024 (SCI-Expanded) identifier

  • Publication Type: Article / Article
  • Volume: 1317
  • Publication Date: 2024
  • Doi Number: 10.1016/j.molstruc.2024.139106
  • Journal Name: Journal of Molecular Structure
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Chemical Abstracts Core, Chimica, Compendex, INSPEC
  • Keywords: Alzheimer's disease, Cholinesterase inhibitory activity, Molecular docking, Multi-target-directed ligands, Neuroprotective effect
  • Gazi University Affiliated: Yes

Abstract

In the current study, three series of new compounds were designed and synthesized through hit optimization, based on the hit compound with a structure (E)-N-(4-{[benzyl(methyl)amino]methyl}thiazol-2-yl)-3-(3,4-dimethoxyphenyl)prop‑2-enamide, which was found as a potential multifunctional anti-Alzheimer agent in our previous study. Then, the biological activities of synthesized compounds (4a-c, 13a-b and 15a-c) were evaluated. The results indicated that 4b, a 2-phenoxyacetamide derivative, exhibited good multifunctional activities. Namely, compound 4b displayed better BChE inhibition (BChE IC50 = 2.10 µM) and antioxidant activity (ORAC = 1.18 Trolox equivalents) compared to the hit compound (BChE IC50 = 14.70 µM, ORAC = 0.5 Trolox equivalents). Additionally, 4b was able to chelate all tested biometals and it also exhibited a neuroprotective effect (63 %), comparable to reference ferulic acid (77 %) while maintaining its safety upon PC12 cell line. When it comes to lowering the levels of TNF-α, NO, IL-1β, and IL-6, 4b performed better activity, relative to the other synthesized compounds. Subsequently, in silico studies such as physicochemical properties, density functional theory (DFT) computational approach and molecular docking studies were performed.