Research Article Biological Evaluation of Newly Synthesized Biaryl Guanidine Derivatives to Arrest β-Secretase Enzymatic Activity Involved in Alzheimer’s Disease Sayyad Ali, 1,2 Muhammad Hassham Hassan Bin Asad , 1,3 Fahad Khan, 4 Ghulam Murtaza , 5 Albert A. Rizvanov , 3 Jamshed Iqbal, 1 Borhan Babak, 2 and Izhar Hussain 1 1 Department of Pharmacy, COMSATS University Islamabad, Abbottabad Campus, 22060, Pakistan 2 Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, USA 3 Department of Genetics, Institute of Fundamental Medicine and Biology, Kazan Federal University, 420021, Russia 4 School of Packaging, Michigan State University, East Lansing, Michigan 48824-1223, USA 5 Department of Pharmacy, COMSATS University Islamabad, Lahore Campus, Pakistan Correspondence should be addressed to Muhammad Hassham Hassan Bin Asad; hasshamasad@yahoo.com and Izhar Hussain; izharhussain@ciit.net.pk Received 29 June 2019; Revised 20 March 2020; Accepted 17 April 2020; Published 11 May 2020 Academic Editor: Hugo Gutiérrez-De-Terán Copyright © 2020 Sayyad Ali et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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 (IC 50 = 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 P o/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. 1. Introduction Alzheimer’s disease (AD) is a continuous neurodegenerative disorder that leads to mental deterioration particularly in geriat- ric 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 inflamma- tion and eventually loss of neurons [1, 2]. Indeed, Aβ peptide accumulation resulted from degradation of β-amyloid precur- sor 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 con- trol AD. The biological inhibition of BACE1 was focused to inhibit Aβ formation [2–4]. Statin-type structures were developed initially to lock the two aspartic acids in the catalytic domain; however, these ligands showed very low penetration into the brain. Later on, cyclic and rigid conformational structures (heterocyclic nucleus for enzyme inhibition) were recognized to improve blood-brain barrier (BBB) circulation [5, 6]. To the best of our knowledge, guanidine derivatives have been documented previously to antagonize nervous disorders, cited by Gerritz et al. as acyl guanidines [6, 7]. We substituted the “acyl” por- tion with biaryl moieties to find out its inhibition results on Hindawi BioMed Research International Volume 2020, Article ID 8934289, 11 pages https://doi.org/10.1155/2020/8934289