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

Digambar Kumar Waiker; Akash Verma; T A Gajendra; Namrata; Anima Roy; Pradeep Kumar; Surendra Kumar Trigun; Saripella Srikrishna; Sairam Krishnamurthy; Vincent Jo Davisson; Sushant Kumar Shrivastava

doi:10.1016/j.ejmech.2024.116409

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

Eur J Med Chem. 2024 Apr 16:271:116409. doi: 10.1016/j.ejmech.2024.116409. Online ahead of print.

Affiliations

¹ Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology - Banaras Hindu University, Varanasi, 221005, India.
² Neurotherapeutics Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology-Banaras Hindu University, Varanasi, 221005, India.
³ Department of Zoology, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
⁴ Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005, India.
⁵ Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA.
⁶ Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology - Banaras Hindu University, Varanasi, 221005, India. Electronic address: skshrivastava.phe@itbhu.ac.in.

PMID: 38663285
DOI: 10.1016/j.ejmech.2024.116409

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 (IC₅₀ value = 0.486 ± 0.047 μM), BACE-1 inhibition (IC₅₀ 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 (IC₅₀ 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.

Keywords: Acetylcholine esterase (AChE); Alzheimer's disease; Amyloid-β; Butyrylcholine esterase (BChE); Structure-based drug design; β-Secretase-1.