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A novel synthetic derivative of biaryl guanidine as a potential BACE1 inhibitor, to treat Alzheimer's disease: In-silico, in-vitro and in-vivo evaluation
Author(s)
Sayyad Ali Department of Pharmacy, COMSATS University Islamabad, Abbottabad Campus, Pakistan; Department of Chemistry, Michigan State University, East Lansing, Michigan, U.S.A
Muhammad Hassham Hassan Bin Asad Department of Pharmacy, COMSATS University Islamabad, Abbottabad Campus,,Pakistan
Muhammad Arslan Javed Department of Medicine, Services Institute of Medical Sciences, Services Hospital Lahore,,Pakistan
Tariq Javed Department of Pharmacy, LMDC, University of Health Sciences,Lahore,Pakistan
Yasser MSA Al-Kharaman Department of Pharmacy, COMSATS University Islamabad, Abbottabad Campus,,Pakistan
Muhammad Latif Department of Zoology, Division of Science and Technology, University of Education, Lahore, Pakistan
Sabeeh Mohsin Department of Pharmacy, COMSATS University Islamabad, Abbottabad Campus,,Pakistan
Taufiq Nawaz Department of Food Sciences and Technology, The University of Agriculture,Peshawar,Pakistan
Syed Muhammad Farid Hasan Department of Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi,Karachi,Pakistan
Jamshed Iqbal Department of Pharmacy, COMSATS University Islamabad, Abbottabad Campus,,Pakistan
Borhan Babak Department of Chemistry, Michigan State University,East Lansing, Michigan,U.S.A
Izhar Hussain Department of Pharmacy, COMSATS University Islamabad, Abbottabad Campus,,Pakistan
Abstract
BACE1 enzyme has been known a potential target involved in Alzheimer's disease (AD). Present research was focused on the principles of virtually screening, chemical synthesis and protease inhibitory effect of BACE1 enzyme via biaryl guanidine derivatives. In-silico based paradigm (ligand binding interaction within active domain of BACE 1 enzyme i.e., aspartate Asp32 and Asp228) a novel compound was synthesized and subsequently subjected to in-vitro and in-vivo evaluation. 1,3-di(isoquinolin-6-yl) guanidine was synthesized and found potent (IC50 6±0.56 µM) and active to arrest (99 %) ß-secretase enzyme (FRET assay). Furthermore, it was found to improve novel object recognition test (RTI =56.55%) and Morris water maze test (32.26±3.45s) significantly (p<0.05). Enhanced pharmacokinetics and related properties (high iLOGP and Log S =-3.98) along with improved permeation to the blood brain barrier (BBB) (zero Lipinski violation) made it feasible to inhibit BACE1 as a novel therapeutic source to treat AD in future.
Publication Details
Page(s) 1339-1345
DOI 10.36721/PJPS.2022.35.5.REG.1339-1345.1
Published Journal: Pakistan Journal of Pharmaceutical Sciences, Volume: 35, Issue: 5, Year: 2022
Keywords
Inhibition Alzheimers Disease BACE1 Biaryl guanidine
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