ARTICLE Exploring beta amyloid cleavage enzyme-1 inhibition and neuroprotective role of benzimidazole analogues as anti-alzheimer agents Archana S. Gurjar | Vivek S. Solanki | Ankita R. Meshram | Suchita S. Vishwakarma Department of Pharmaceutical Chemistry, Principal K. M. Kundnani College of Pharmacy, Mumbai, India Correspondence Archana S. Gurjar, Department of Pharmaceutical Chemistry, Principal K. M. Kundnani College of Pharmacy, 23 Jote Joy, R. S. Marg, Cuffe Parade, Mumbai 400 005, India. Email: gurjaras@gmail.com Funding information University of Mumbai, Grant/Award Numbers: Minor Research Project Grant 509, APD/ICD/2018-19 Abstract Beta amyloid cleavage enzyme-1 (BACE1) is the key enzyme involved in Aβ peptide formation in Alzheimer's disease pathogenesis. We intend to target this enzyme by exploring benzimidazole analogues against BACE1 as potential anti-Alzheimer agents. Docking studies were performed to determine the hydrogen bond interactions between the designed molecules and the target protein's active site. Research indicates the relationship between oxidative stress and Aβ effect in precipitating neurodegeneration; hence, the series was also studied in vitro to ascertain its neuroprotective role by performing the lipid peroxidation assay. In silico absorption, distribution, metabolism, and excretion studies were undertaken to assess the drug-like suitability of the ana- logues. To judge the effect of the synthesized analogues on central nervous sys- tem (CNS), toxicity and memory model studies were conducted on mice. Thus, overall results showcase analogues 11 and 14 as the most promising ones with the dual role of BACE1 inhibition and neuroprotection, along with memory retention. KEYWORDS BACE1, docking, in silico ADME studies, in vitro LPO assay, memory model studies, toxicity study 1 | INTRODUCTION Alzheimer's disease (AD) is an advancing multifaceted neurodegenerative disorder resulting in the loss of the neurons and intellectual abilities including memory and reasoning, which imposes tremendous emotional, social, and economic burden on the patient, his or her family, and the community. [1,2] Several hypotheses have been proposed to be involved in the etiopathogenesis of AD such as beta amyloid (Aβ) formation and its accumula- tion, Tau (τ) hyperphosphorylation and aggregation, neurotransmitter imbalance, oxidative stress, and others including calcium dysregulation and inflammation. [3] Amongst the etiological factors, beta amyloid cleavage enzyme-1 (BACE1, beta-secretase) is the key enzyme responsible for the formation of Aβ peptides. BACE1 is a type I transmembrane enzyme with high concentration in neurons and belongs to the same retroviral and pepsin aspartic protease family. It has an optimum acidic pH with the correct sequence specificity for the processing of amyloid precursor protein (APP), leading to an increased Aβ generation. [4,5] It regulates a range of neuronal Received: 21 May 2019 Revised: 4 October 2019 Accepted: 13 October 2019 DOI: 10.1002/jccs.201900200 © 2019 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim J Chin Chem Soc. 2019;1–10. http://www.jccs.wiley-vch.de 1