Brain Disorders 7 (2022) 100041 Available online 7 June 2022 2666-4593/© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- nc-nd/4.0/). Structure-Based Drug Design of Novel Piperazine Containing Hydrazone Derivatives as Potent Alzheimer Inhibitors: Molecular Docking and Drug Kinetics Evaluation Abduljelil Ajala * , Adamu Uzairu, Gideon A. Shallangwa, Stephen E. Abechi Department of Chemistry, Faculty of Physical Sciences, Ahmadu Bello University, P.M.B. 1044, Zaria, Kaduna State, Nigeria A R T I C L E INFO Keywords: Alzheimer disease Computer-aided drug design Complex mechanism Binding energy Design Pharmacokinetics ABSTRACT Alzheimer’s disease (AD) is a neurodegenerative disorder that causes dementia and cognitive impairment in the elderly. The exact mechanism of the disease is still unknown. There are four medications available, all of which have a slew of negative side effects and only serve to improve patients’ warning symptoms. Medicinal chemists are looking for treatments for this illness. The development and application of a novel class of multifunctional small molecule inhibitors is discussed. A variety of compounds were synthesized using the hydrazone scaffold. This is due to the ability of hydrazone derivatives to interfere with Amyloid beta (A) self-assembly, which is one of the causative agents in fbrils and oligomers. they can also counteract the impacts of toxic substances free radicals on useful therapeutic agents such as central nervous system penetrant drugs. In this study, structure- based drug design techniques utilized. Based on established literature studies and reasons such as lower reso- lution value (2.35), no mutation, Homo Sapiens, and X-ray diffraction method, a protein target (code ID 4EY7) was chosen. The protein target was designed to interact with compounds of interest (a lead compound with a higher binding energy), and was used as a template to design ffteen Hydrazone derivatives with greater in- teractions, higher binding scores, and improved enhanced drug-like properties and drug kinetic parameters The fndings of these studies can be used to create promising pharmacotherapeutic compounds for the treatment of AD. Introduction Alzheimer’s disease (AD) is a chronic neurodegenerative abnormal- ity associated with dementia and cognitive impairment that primarily affects the elderly [1]. A detailed ailment mechanism, however, is still yet to be explained. Several studies have found that neuro-infammation associated with amyloid-beta (A) deposition [2] is a major contributor to the pathology of neurodegenerative syndromes in the brain. As a result, the infammatory process in neurodegeneration necessitates immediate action to break this connection [3]. Recent studies have revealed that compounds containing the hydrazone moiety exhibit a variety of biological activities [4]. Currently, pharmacologically active hydrazone derivatives with anti-neuroinfammatory potential are being investigated as potential treatments for Alzheimer’s disease [5]. Based on these fndings, a new class of hydrazone derivatives was created. This combination of studies lends support to the development of novel and effcient agents for the treatment of Alzheimer’s disease [6], and is being carried out with the help of structure-based drug design. Current research is focused on identifying potential hydrazine de- rivatives that could be used as drug candidates. The derivatives of hydrazone were identifed using structure-based drug design, drug characteristics, molecular docking, and increased bonding with the Human Acetylcholinesterase receptor (4EY7), which is recognized to fnalize the relevant complex for the treatment of AD [7–8]. The focus of this research was to perform Molecular Docking of hydrazone with Human Acetylcholinesterase to examine the binding orientation and affnities of hydrazone in attempt to comprehend how Abbreviations: AD, Alzheimer Disease; SA, Synthetic Accessibility; BA, Brenk alerts; BS, Bioavailability Score; MV, Muegge violations; EV, Egan violations; VV, Veber violations; GV, Ghose violations; LV, Lipinski violations; HIA, Human gastrointestinal absorption; BBB, blood–brain barrier penetration; EI, Enzyme Inhibitor; BS, Bioactivity Score. * Corresponding author. E-mail address: abdulajala39@gmail.com (A. Ajala). Contents lists available at ScienceDirect Brain Disorders journal homepage: www.sciencedirect.com/journal/brain-disorders https://doi.org/10.1016/j.dscb.2022.100041