Department Of Chemistry
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Item Efficient synthesis and mechanistic insights for the formation of imidazo[1,2-a]pyridines via multicomponent decarboxylative coupling using chitosan-supported copper catalysts(Elsevier B.V., 2023-10-03T00:00:00) Kaur, Pavneet; Gurjar, Kamlesh K.; Arora, Tania; Bharti, Divya; Kaur, Manpreet; Kumar, Vinod; Parkash, Jyoti; Kumar, RakeshAn efficient multicomponent decarboxylative coupling of 2-aminopyridines, aldehydes and alkynoic acids for the synthesis of imidazo[1,2-a]pyridines was developed using recyclable chitosan-supported copper (chit@CuSO4) as a heterogeneous catalyst. Computational and experimental evidence revealed that in situ generated propargylamine undergoes cyclization to the desired imidazopyridine via prototropic isomerization involving allene type intermediates. Control experiments on isolated propargylamine demonstrated that cyclization could proceed without any metal catalyst. In literature, the cyclization step is assumed to be facilitated by metal catalyst and experimental proof for the involvement of actual intermediates is not available. The synthesized imidazopyridines were further evaluated for antiproliferative activity against human neuroblastoma cells (SHSY-5Y) using MTT assay. � 2023 Elsevier B.V.Item Chitosan-supported FeCl3 catalyzed multicomponent synthesis of tetrahydroisoquinoline-indole hybrids with promising activity against chloroquine resistant Plasmodium falciparum(Elsevier B.V., 2022-10-26T00:00:00) Kaur, Pavneet; Sharma, Priyanka; Kumar, Vinod; Sahal, Dinkar; Kumar, RakeshAn operationally simple three-component coupling of tetrahydroisoquinoline (THIQ), aldehydes and indoles or indole-3-carboxylic acids has been achieved using chitosan-ionic liquid supported FeCl3 (chit-IL@FeCl3) as a recyclable heterogeneous catalyst. The developed waste-free approach provided rapid access to biologically important THIQ-indole hybrids without the use of any additive or ligand. The synthesized THIQ-indole hybrids were evaluated as antiplasmodial agents against chloroquine-sensitive (Pf3D7) and chloroquine-resistant (PfINDO) strains of Plasmodium falciparum. Compounds 4b (most potent against Pf3D7) and 4g (most potent against PfINDO) showed IC50 values of 1.32 and 0.26 �g/mL respectively. Also, 4g showed strong cytocidal action against both rings and trophozoite stages. Furthermore, cytotoxic study against human liver HUH 7 cells revealed that the most potent compound 4g with an excellent resistance index of 0.07 is also relatively non-toxic. The results of this study suggest that THIQ-indole hybrids hold an enormous potential for developing new antimalarial agents with novel mechanism of action. � 2022 Elsevier B.V.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.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 Recent synthetic strategies for monocyclic azole nucleus and its role in drug discovery and development(Bentham Science Publishers B.V., 2018) Neha; Dwivedi, Ashish Ranjan; Kumar, Rakesh; Kumar, VinodBackground: In recent years, the development and diversification of heterocyclic compounds has become central to the discovery of bioactive compounds with novel or improved pharmacological properties. In particular, N-containing heterocycles are proved to be promising leads and drug candidates, and received huge attention of the medicinal chemists. Objective: Many drugs especially antibiotics are becoming obsolete due to the development of multidrug resistance. Moreover, toxicity and other side effects of some drugs necessitated the quest for safer and more potent drug candidates. The current review article described biological potential of various monocyclic azoles. Recent developments in the synthesis of azole derivatives have been also reviewed. Conclusion: The presence of N-heterocyclic rings can influence the pharmacokinetics, pharmacodynamics, pKa and bioavailability profile of the drug molecules. Compounds containing monocyclic azole rings showed various biological activities and number of molecules are in clinical practice. A number of important leads and potential drug candidates containing azole nucleus are in advance stages of drug developments. Thus, simple, atom economic and more efficient synthetic strategies are desired for the synthesis of new libraries of the compounds. ? 2018 Bentham Science Publishers.Item 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.