Biological Evaluation of Newly Synthesized Biaryl Guanidine Derivatives to Arrest β-Secretase Enzymatic Activity Involved in Alzheimer's Disease.

Sayyad Ali,Jamshed Iqbal,Izhar Hussain,Borhan Babak,Ghulam Murtaza,Fahad Khan,Muhammad Hassham Hassan Bin Asad,Albert A Rizvanov

doi:10.1155/2020/8934289

Abstract

Proteases BACE1 (β-secretases) enzymes have been recognized as a promising target associated with Alzheimer's disease (AD). This study was carried out on the principles of molecular docking, chemical synthesis, and enzymatic inhibition of BACE1 enzymes via biaryl guanidine-based ligands. Based on virtual screening, thirteen different compounds were synthesized and subsequently evaluated via in vitro and in vivo studies. Among them, 1,3-bis(5,6-difluoropyridin-3-yl)guanidine (compound (9)) was found the most potent (IC50 = 97 ± 0.91 nM) and active to arrest (99%) β-secretase enzymes (FRET assay). Furthermore, it was found to improve the novel object recognition test and Morris water maze test significantly (p < 0.05). Improved pharmacokinetic parameters, viz., Log Po/w (1.76), Log S (-2.73), and better penetration to the brain (BBB permeation) with zero Lipinski violation, made it possible to hit the BACE1 as a potential therapeutic source for AD.

Highlights

Alzheimer’s disease (AD) is a continuous neurodegenerative disorder that leads to mental deterioration in geriatric population
This study reported a series of thirteen newly synthesized biaryl guanidine ligands intended to inhibit β-secretase enzymes
The combined effects strengthened the amyloid cascade hypothesis, targeting BACE1 as a therapeutic strategy to stop the progression of AD

Summary

Introduction

Alzheimer’s disease (AD) is a continuous neurodegenerative disorder that leads to mental deterioration in geriatric population. It is characterized by serious loss of cognition and social and psychiatric anomalies [1, 2]. Amyloid-β (Aβ) peptide deposition and agglutination of tau proteins are the main pathologic features of the disease that led to the inflammation and eventually loss of neurons [1, 2]. Aβ peptide accumulation resulted from degradation of β-amyloid precursor proteins (APP) via β and γ secretase enzymes. The beta site APP cleaving enzyme (BACE1) (composed of 501 extracellular and 22 cytoplasmic amino acids domains) is a main player of producing Aβ plaques and a promising inhibiting target to control AD. The biological inhibition of BACE1 was focused to inhibit Aβ formation [2,3,4]

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Conclusion