#42 Ligand-based drug design for search of imidazole analogues as anti-Alzheimer agents

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder. Currently, more than 50 million people are suffering from dementia worldwide. Neuropathologically it is characterized by the presence of extracellular Amyloid β (Aβ) plaques and intracellular neurofibrillary Tau protein tangles in the brain. Literature reveals that a crucial target to relieve symptoms of AD is Acetylcholinesterase (AChE). Many heterocyclic compounds have been developed in past years as AChE inhibitors. The marketed ones are Donepezil, Rivastigmine, and Galantamine, all are nitrogen-containing drugs that have potential activity towards AChE. We have focused on a series of imidazole as AChE inhibitors. This scaffold was chosen due to its similarity with previously reported benzimidazole derivatives as AChE inhibitors. Computer-aided drug discovery broadly encompasses structure-based and ligand-based models. Ligand-based drug design (LBDD) methods mainly include pharmacophore modeling and QSAR (quantitative structure-activity relationship). These methods use ligand information for predicting the biological activity of test series, based on similarity/dissimilarity with structural features of previously known active ligands. Ligands were sketched and minimized with LigPrep3 (Schrodinger). In-silico ADME (Absorption, Distribution, Metabolism, Excretion) studies were accomplished using the QikProp V5.5 module (Schrodinger). Pharmacophore modeling was done using Phase V5.4 (Schrodinger). The atom-based 3D-QSAR software of Schrodinger’s Maestro release 2018-1.10 was used for QSAR studies. Various sets of molecules with a wide range of AChE inhibitory activity were chosen from the literature to get a robust model for hypotheses generation. Created hypotheses were three to five points model. The entire series of minimized analogues were screened upon the shortlisted hypotheses to align them and carried further for QSAR studies. Analogues showcasing favorable pharmacokinetic properties and good predicted activity from LBDD were subjected to synthesis. Characterization was performed by IR and NMR spectrometric techniques. Results of the in silico ADME studies predicted that all the analogues showcase drug likeness. LBDD study revealed that IM-1, IM-2, IM-7, and IM-18 exhibited nearly the same predicted activity as Donepezil, hence they may show good inhibitory AChE activity. Analogues that depict good activity can be subjected to in vitro pharmacological evaluations such as lipid peroxidation assay to assess the neuroprotective role, cholinesterase inhibition, and memory model study.