Back to Search
Start Over
Design, synthesis, and biological evaluation of some 2-(3-oxo-5,6-diphenyl-1,2,4-triazin-2(3H)-yl)-N-phenylacetamide hybrids as MTDLs for Alzheimer's disease therapy.
- Source :
-
European Journal of Medicinal Chemistry . May2024, Vol. 271, pN.PAG-N.PAG. 1p. - Publication Year :
- 2024
-
Abstract
- Inspite of established symptomatic relief drug targets, a multi targeting approach is highly in demand to cure Alzheimer's disease (AD). Simultaneous inhibition of cholinesterase (ChE), β secretase-1 (BACE-1) and Dyrk1A could be promising in complete cure of AD. A series of 18 diaryl triazine based molecular hybrids were successfully designed, synthesized, and tested for their hChE, hBACE-1, Dyrk1A and Aβ aggregation inhibitory potentials. Compounds S-11 and S-12 were the representative molecules amongst the series with multi-targeted inhibitory effects. Compound S-12 showed hAChE inhibition (IC 50 value = 0.486 ± 0.047 μM), BACE-1 inhibition (IC 50 value = 0.542 ± 0.099 μM) along with good anti -Aβ aggregation effects in thioflavin-T assay. Only compound S-02 of the series has shown Dyrk1A inhibition (IC 50 value = 2.000 ± 0.360 μM). Compound S-12 has also demonstrated no neurotoxic liabilities against SH-SY5Y as compared to donepezil. The in vivo behavioral studies of the compound S-12 in the scopolamine- and Aβ-induced animal models also demonstrated attanuation of learning and memory functions in rats models having AD-like characteristics. The ex vivo studies, on the rat hippocampal brain demonstrated reduction in certain biochemical markers of the AD brain with a significant increase in ACh level. The Western blot and Immunohistochemistry further revealed lower tau, APP and BACE-1 molecular levels. The drosophilla AD model also revealed improved eyephenotype after treatment with compound S-12. The molecular docking studies of the compounds suggested that compound S-12 was interacting with the ChE-PAS & CAS residues and catalytic dyad residues of the BACE-1 enzymes. The 100 ns molecular dynamics simulation studies of the ligand-protein complexed with hAChE and hBACE-1 also suggested stable ligand–protein confirmation throughout the simulation run. [Display omitted] • A series of 18 compounds (S 01-18) was designed based on the molecular hybridization and in silico approaches. • Compounds S-11 and S-12 have shown good BBB permeation and in vitro multi-targeted inhibitory efficacy. • Compound S-12 demonstrated attenuation of learning and memory functions in in vivo rat and Drosophila models. • Compound S-12 revealed lower tau, APP and BACE-1 molecular expressions in molecular mechanistic ex vivo studies. • Compound S-12 showed good oral bioavailability via pharmacokinetic studies. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02235234
- Volume :
- 271
- Database :
- Academic Search Index
- Journal :
- European Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 177147428
- Full Text :
- https://doi.org/10.1016/j.ejmech.2024.116409