Department Of Chemistry
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Item Design, Synthesis, and Pharmacological Evaluation of N-Propargylated Diphenylpyrimidines as Multitarget Directed Ligands for the Treatment of Alzheimer's Disease(American Chemical Society, 2022-07-07T00:00:00) Kumar, Bhupinder; Dwivedi, Ashish Ranjan; Arora, Tania; Raj, Khadga; Prashar, Vikash; Kumar, Vijay; Singh, Shamsher; Prakash, Jyoti; Kumar, VinodAlzheimer's disease (AD), a multifactorial complex neural disorder, is categorized with progressive memory loss and cognitive impairment as main clinical features. The multitarget directed ligand (MTDL) strategy is explored for the treatment of multifactorial diseases such as cancer and AD. Herein, we report the synthesis and screening of 24 N-propargyl-substituted diphenylpyrimidine derivatives as MTDLs against acetylcholine/butyrylcholine esterases and monoamine oxidase enzymes. In this series, VP1 showed the most potent MAO-B inhibitory activity with an IC50value of 0.04 � 0.002 ?M. VP15 with an IC50value of 0.04 � 0.003 ?M and a selectivity index of 626 (over BuChE) displayed the most potent AChE inhibitory activity in this series. In the reactive oxygen species (ROS) inhibition studies, VP1 reduced intercellular ROS levels in SH-SY5Y cells by 36%. This series of compounds also exhibited potent neuroprotective potential against 6-hydroxydopamine-induced neuronal damage in SH-SY5Y cells with up to 90% recovery. In the in vivo studies in the rats, the hydrochloride salt of VP15 was orally administered and found to cross the blood-brain barrier and reach the target site. VP15�HCl significantly attenuated the spatial memory impairment and improved the cognitive deficits in the mice. This series of compounds were found to be irreversible inhibitors and showed no cytotoxicity against neuronal cells. In in silico studies, the compounds attained thermodynamically stable orientation with complete occupancy at the active site of the receptors. Thus, N-propargyl-substituted diphenylpyrimidines displayed drug-like characteristics and have the potential to be developed as MTDLs for the effective treatment of AD. � 2022 American Chemical Society. All rights reserved.Item Advancements in the development of multi-target directed ligands for the treatment of Alzheimer's disease(Elsevier Ltd, 2022-04-05T00:00:00) Kumar, Naveen; Kumar, Vijay; Anand, Piyush; Kumar, Vinay; Ranjan Dwivedi, Ashish; Kumar, VinodAlzheimer's disease (AD) is a multifactorial irreversible neurological disorder which results in cognitive impairment, loss of cholinergic neurons in synapses of the basal forebrain and neuronal death. Exact pathology of the disease is not yet known however, many hypotheses have been proposed for its treatment. The available treatments including monotherapies and combination therapies are not able to combat the disease effectively because of its complex pathological mechanism. A multipotent drug for AD has the potential to bind or inhibit multiple targets responsible for the progression of the disease like aggregated A?, hyperphosphorylated tau proteins, cholinergic and adrenergic receptors, MAO enzymes, overactivated N-methyl-D-aspartate (NMDA), ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor etc. The traditional approach of one disease-one target-one drug has been rationalized to one drug-multi targets for the chronic diseases like AD and cancer. Thus, over the last decade research focus has been shifted towards the development of multi target directed ligands (MTDLs) which can simultaneously inhibit multiple targets and stop or slow the progression of the disease. The MTDLs can be more effective against AD and eliminate any possibility of drug-drug interactions. Many important active pharmacophore units have been fused, merged or incorporated into different scaffolds to synthesize new potent drugs. In the current article, we have described various hypothesis for AD and effectiveness of the MTDLs treatment strategy is discussed in detail. Different chemical scaffolds and their synthetic strategies have been described and important functionalities are identified in the chemical scaffold that have the potential to bind to the multiple targets. The important leads identified in this study with MTDL characteristics have the potential to be developed as drug candidates for the effective treatment of AD. � 2022 Elsevier LtdItem Investigation of Indole-3-piperazinyl Derivatives as Potential Antidepressants: Design, Synthesis, In-Vitro, In-Vivo and In-Silico Analysis(John Wiley and Sons Inc, 2021-11-03T00:00:00) Kumar, Ravi R.; Kumar, Vijay; Kaur, Dilpreet; Nandi, Nilay K.; Dwivedi, Ashish R.; Kumar, Vinod; Kumar, BhupinderDepression is declared the second leading cause of disability worldwide. Recently, cases of depression have increased significantly in adolescents, young adults as well as in elder population. Monoamine oxidase-A (MAO-A) is considered one of the major targets for the treatment of depression. In the current study, we have designed and synthesized various indole functionalized piperazinyl derivatives and evaluated them for in vitro MAO-A inhibitory activity and in vivo antidepressant-like activity. Most of the compounds were found to possess potent MAO-A inhibitory activity with IC50 values in the sub-micromolar range along with significant selectivity over MAO-B. Compounds RP1 and RP9 emerged as the most promising reversible MAO-A inhibitors with IC50 values of 0.11�0.03 ?M and 0.14�0.02 ?M and displayed selectivity of 193 folds and 178 folds over Monoamine oxidase-B (MAO-B), respectively. In the series, RP1 showed good intracellular ROS inhibitory activity along with neuroprotective properties. These compounds were found nontoxic against SH-SY5Y cells and explored antidepressant activities. In the in vivo Forced swimming test (FST) and Tail suspension test (TST) studies, RP1 exhibited potential antidepressant-like behavior similar to standard drug fluoxetine while compound RP9 showed antidepressant-like activity only in the TST studies. The molecular docking and dynamics studies further supported the results obtained in the in vitro and in vivo studies. Thus, the indole functionalized piperazinyl derivatives were found to be promising ligands and can be developed as new antidepressant molecules. � 2021 Wiley-VCH GmbHItem A Review on the Arylpiperazine Derivatives as Potential Therapeutics for the Treatment of Various Neurological Disorders(Bentham Science Publishers, 2022-01-18T00:00:00) Kumar, Bhupinder; Kumar, Naveen; Thakur, Amandeep; Kumar, Vijay; Kumar, Rakesh; Kumar, VinodNeurological disorders are disease conditions related to the neurons and central nervous system (CNS). Any structural, electrical, biochemical, and functional abnormalities in neurons can lead to various types of disorders, like Alzheimer�s disease (AD), depression, Parkinson�s disease (PD), epilepsy, stroke, etc. Currently available medicines are symptomatic and do not treat the disease state. Thus, novel CNS active agents with the potential to completely treat an illness are highly desired. A range of small organic molecules is being explored as potential drug candidates to cure different neurological disorders. In this context, arylpiperazinehas been found to be a versatile scaffold and indispensable pharmacophore in many CNS active agents. Several molecules with arylpiperazine nucleus have been developed as potent leads for the treatment of AD, PD, depression, and other disorders. The arylpiperazine nucleus can be optionally substituted at different chemical structures and offer flexibility for the synthesis of a large number of derivatives. In the current review article, we have explored the role of various arylpiperazine containing scaffolds against different neurological disorders, including AD, PD, and depression. The structure-activity relationship studies were conducted for recognizing potent lead compounds. This review article may provide important insights into the structural requirements for designing and synthesizing effective molecules as curative agents for different neurological disorders. � 2022 Bentham Science Publishers.