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 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.Item Multi-Target-Directed Ligands as an Effective Strategy for the Treatment of Alzheimer�s Disease(Bentham Science Publishers, 2021-05-12T00:00:00) Kumar, Bhupinder; Thakur, Amandeep; Dwivedi, Ashish Ranjan; Kumar, Rakesh; Kumar, VinodAlzheimer�s disease (AD) is a complex neurological disorder and multiple pathological factors are believed to be involved in the genesis and progression of the disease. A number of hypothesis including Acetylcholinesterase, Monoamine oxidase, ?Amyloid, Tau protein etc. have been proposed for the initiation and progression of the disease. At present, acetylcholine esterase inhibitors and memantine (NMDAR antagonist) are the only approved therapy for the symptomatic management of AD. Most of these single-target drugs have miserably failed in the treatment or halting the progression of the disease. Multi-factorial diseases like AD require complex treatment strategies that involve simultaneous modulation of a network of interacting targets. Since last few years, Multi-Target-Directed Ligands (MTDLs) strategy, drugs that can simultaneously hit multiple targets, is being explored as an effective therapeutic approach for the treatment of AD. In the current review article, the authors have briefly described various pathogenic pathways associated with the AD. Importance of Multi-Target-Directed Ligands and their design strategies in recently reported articles have been discussed in detail. Potent leads identified through various structure-activity relationship studies and their drug like characteristics are described. Recently developed promising compounds have been summarized in the article. Some of these MTDLs with balanced activity profile against different targets have the potential to be developed as drug candidates for the treatment of AD. � 2022 Bentham Science Publishers.Item Chitosan-supported copper as an efficient and recyclable heterogeneous catalyst for A3/decarboxylative A3-coupling reaction(Elsevier Ltd, 2018) Kaur, Pavneet; Kumar, Bhupinder; Kumar, Vinod; Kumar, RakeshChitosan-supported copper (chit@copper) based heterogeneous catalysts have been explored for A3-coupling and decarboxylative A3-coupling. The developed protocol employs low catalyst loading, solventless condition and easy work-up for the synthesis of diversely substituted propargylamines. More importantly, the catalyst could be recovered and reused without any significant loss in the activity. This offer huge advantages as recyclability issues are rarely addressed in decarboxylative A3-coupling. Leaching studies were carried out using AAS and ICPMS analysis. It is envisaged that chit@copper catalysts can have potential applications in terms of efficiency and recyclability in the emerging area of decarboxylative C?H bond activation/functionalization strategies. ? 2018 Elsevier LtdItem Mechanisms of tubulin binding ligands to target cancer cells: Updates on their therapeutic potential and clinical trials(Bentham Science Publishers B.V., 2017) Kumar, Bhupinder; Kumar, Rakesh; Skvortsova, Ira; Kumar, VinodBackground: A number of chemically diverse substances bind to the tubulin and inhibit cell proliferation by disrupting microtubule dynamics. There are four binding sites for the ligands binding to the tubulin; taxane/epothilone and laulimalide/peloruside binding ligands stabilize microtubule while vinca and colchicine binding site agents promote microtubule depolymerization. Most of the tubulin binding ligands disturb the tubulin-microtubule dynamic equilibrium but these may exhibit anticancer activities through different mechanisms. Taxanes and epothilones are widely used cytotoxic agents and are found effective against different types of human malignancies. However, taxanes are susceptible to pgp mediated multi-drug resistance, dose limiting hematopoietic toxicity and cumulative neurotoxicity. Vinca alkaloids are already in clinical practice, but ligands binding to the colchicine site are still in the different stages of clinical trials. Objective: In the current review article, plausible mechanistic details about the interactions of ligands at the binding pocket and subsequent changes in the tubulin structure are described. The review article also illustrated different formulations of the tubulin binding agents in combination with other chemotherapeutic agents and their therapeutic potential against various human malignancies. Conclusion: Tubulin targeting agents emerged as one of the most successful anticancer drugs and a number of structurally different chemical compounds are in advance stages of clinical development. ? 2017 Bentham Science Publishers.