Browsing by Author "Kumar, Bhupinder"

Now showing 1 - 19 of 19

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, Rakesh
Chitosan-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 Ltd
Design Strategies, Chemistry and Therapeutic Insights of Multi-target Directed Ligands as Antidepressant Agents
(Bentham Science Publishers, 2021-11-03T00:00:00) Singh, Karanvir; Bhatia, Rohit; Kumar, Bhupinder; Singh, Gurpreet; Monga, Vikramdeep
Depression is one of the major disorders of the central nervous system worldwide and causes disability and functional impairment. According to the World Health Organization, around 265 million people worldwide are affected by depression. Currently marketed antidepressant drugs take weeks or even months to show anticipated clinical efficacy but remain ineffective in treating suicidal thoughts and cognitive impairment. Due to the multifactorial complexity of the disease, single-target drugs do not always produce satisfactory results and lack the desired level of therapeutic efficacy. Recent literature reports have revealed improved therapeutic potential of multi-target directed ligands due to their synergistic potency and better safety. Medicinal chemists have gone to great extents to design multitarget ligands by generating structural hybrids of different key pharmacophores with improved binding affinities and potency towards different receptors or enzymes. This article has compiled the design strategies of recently published multi-target directed ligands as antidepressant agents. Their biological evaluation, structural-activity relationships, mechanistic and in silico studies have also been described. This article will prove to be highly useful for the researchers to design and develop multi-target ligands as antidepressants with high potency and therapeutic efficacy. � 2022 Bentham Science Publishers.
Design, Synthesis and Evaluation of Donepezil-Rasagiline Based Compounds as Multipotent Inhibitors for the Treatment of Alzheimer’s Disease
(Central University of Punjab, 2019) Kumar, Bhupinder; Kumar, Vinod
Alzheimer’s disease (AD) is multifactorial in nature and different enzymes including MAO, AChE, and amyloid beta are implicated in its pathogenesis. The pathomechanism of AD is complex in nature and single target drugs proved to be ineffective for the treatment of the disease. With an aim of developing dual/multipotent inhibitors, 4,6- diphenylpyrimidines were optionally substituted with propargyl group and an ethyl chain containing a cyclic or acyclic tertiary nitrogen atom (piperidine/morpholine/pyrrolidine/N,N-dimethyl) as potential pharmacophores for MAO and AChE enzymes. Compound VB1 was found to be the most potent MAO-A (IC50 value of 18.34 ± 0.38 nM) inhibitor and VB8 was found to be the most potent AChE (IC50 value of 9.54 ± 0.07 nM) inhibitor. Compound VB3 was another promising compound in series-I with IC50 values of 28.33 ± 3.22 nM and 18.92 ± 0.29 nM against MAO-A and AChE, respectively and displayed very high selectivity index (103) for AChE over BuChE. These compounds were found to be reversible inhibitors of MAO and AChE enzymes and non-toxic to the human neuroblastoma SH-SY5Y cells. Based on structure-activity relationship analysis of the first series of compounds, second series of the compounds were designed by fixing the position of piperidine/morpholine ethyl chain at the para position of one of the phenyl rings. In the second series, compound VP15 v was found to be a multi-potent inhibitor of MAO-B and AChE with IC50 values of 0.37 ± 0.03 μM and 0.04 ± 0.003 μM, respectively. VP15 was found to be selective for MAOB with selectivity index of 270 over MAO-A. It also displayed SI of 625 for AChE over BuChE. VP15 was found to be irreversible inhibitor of MAO-B. In the third series of target compounds, both the phenyl rings of diphenylpyrimidines were substituted with O-propargyl groups. Different derivatives have been synthesized with O-propargyl groups substituted at ortho, meta and para positions of the phenyl rings. In the third series of compounds, AVB1 and AVB4 were found to be the most potent inhibitors of AChE and MAO-B with IC50 values of 1.35 ±0.03 μM and 1.49 ± 0.09 μM, respectively. In the reversible inhibition studies, the lead compounds were found to be reversible inhibitors of MAO-B and AChE enzymes. In the ROS protection inhibition studies, AVB1 and AVB4 displayed good activity in SH-SY5Y cells and AVB1 reduced the ROS levels up to 30% at 5 μM. This series of compounds were also found to be non-toxic to the SH-SY5Y cells in the cytotoxicity studies. Thus, from the present study it can be concluded that 4,6-diphenylpyrimidine derivatives can act as potential lead for the development of effective drug candidates for the treatment of AD. Compound VB3 and VP15 were found to be the most potent dual inhibitors of MAO and AChE.
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, Vinod
Alzheimer'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.
Dipropargyl substituted diphenylpyrimidines as dual inhibitors of monoamine oxidase and acetylcholinesterase
(Elsevier, 2019) Kumar, Bhupinder; Kumar, V; Prashar, V; Saini, S; Dwivedi, A.R; Bajaj, B; Mehta, D; Parkash, Jyoti; Kumar, Vinod
Alzheimer's disease (AD) is a multifactorial neurological disorder involving complex pathogenesis. Single target directed drugs proved ineffective and since last few years' different pharmacological strategies including multi-targeting agents are being explored for the effective drug development for AD. A total of 19 dipropargyl substituted diphenylpyrimidines have been synthesized and evaluated for the monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibition potential. All the compounds were found to be selective and reversible inhibitors of MAO-B isoform. These compounds also displayed good AChE inhibition potential with IC50 values in low micromolar range. AVB4 was found to be the most potent MAO-B inhibitor with IC50 value of 1.49 ± 0.09 μM and AVB1 was found to be the most potent AChE inhibitor with IC50 value of 1.35 ± 0.03 μM. In the ROS protection inhibition studies, AVB1 and AVB4 displayed weak but interesting activity in SH-SY5Y cells. In the cytotoxicity studies involving SH-SY5Y cells, both AVB1 and AVB4 were found to be non-toxic to the tissue cells. In the molecular dynamic simulation studies of 30 ns, the potent compounds were found to be quite stable in the active site of MAO-B and AChE. The results suggested that AVB1 and AVB4 are promising dual inhibitors and have the potential to be developed as anti-Alzheimer's drug. © 2019
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, Bhupinder
Depression 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 GmbH
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, Vinod
Background: 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.
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, Vinod
Alzheimer�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.
A Perspective on Monoamine Oxidase Enzyme as Drug Target: Challenges and Opportunities
(2017) Kumar, Bhupinder; Gupta, Vivek Prakash; Kumar, Vinod
The monoamine oxidase (MAO) enzyme is responsible for the deamination of monoamine neurotransmitters and regulates their concentration in the central and peripheral nervous systems. Imbalance in the concentration of neurotransmitters in the brain and central nervous system is linked with the biochemical pathology of various neurogenic disorders. Irreversible MAO inhibitors were the first line drugs developed for the management of severe depression but most of these were withdrawn from the clinical practice due to their fatal side effects including food-drug interactions. New generations of MAO inhibitors were developed which were reversible and selective for one of the enzyme isoform and showed improved pharmacological profile. The discovery of crystal structure of MAO-A & MAO-B isoforms helped in understanding the drug-receptor interactions at the molecular level and designing of ligands with selectivity for either of the isoforms. The current article provides an overview on the MAO enzyme as potential drug target for different disease states. The article describes catalytic mechanism of MAO enzyme, crystal structures of the two MAO isoforms, traditional MAO inhibitors and various problems associated with their use, new developments in the MAO inhibitors and their potential as therapeutic agents especially in neurological disorders.
Promising targets in anti-cancer drug development: Recent updates
(Bentham Science Publishers B.V., 2017) Kumar, Bhupinder; Singh, Sandeep; Skvortsova, Ira; Kumar, Vinod
Cancer is a multifactorial disease and its genesis and progression are extremely complex. The biggest problem in the anticancer drug development is acquiring of multidrug resistance and relapse. Classical chemotherapeutics directly target the DNA of the cell, while the contemporary anticancer drugs involve molecular-targeted therapy such as targeting the proteins possessing abnormal expression inside the cancer cells. Conventional strategies for the complete eradication of the cancer cells proved ineffective. Targeted chemotherapy was successful in certain malignancies however, the effectiveness has often been limited by drug resistance and side effects on normal tissues and cells. Since last few years, many promising drug targets have been identified for the effective treatment of cancer. The current review article describes some of these promising anticancer targets that include kinases, tubulin, cancer stem cells, monoclonal antibodies and vascular targeting agents. In addition, promising drug candidates under various phases of clinical trials are also described. Multi-acting drugs that simultaneously target different cancer cell signaling pathways may facilitate the process of effective anti-cancer drug development. ? 2017 Bentham Science Publishers.
Recent developments on 1,2,4-triazole nucleus in anticancer compounds: A review
(Bentham Science Publishers B.V., 2016) Kaur, Ramandeep; Dwivedi, Ashish Ranjan; Kumar, Bhupinder; Kumar, Vinod
1,2,4 triazole is an important nucleus present in a large number of compounds. More than thirty-five compounds containing this nucleus are introduced into the market. 1,2,4-triazole nucleus is stable to metabolism and acts as an important pharmacophore by interacting at the active site of a receptor as hydrogen bond acceptor and as a donor. Due to its polar nature, the triazole nucleus can increase the solubility of the ligand and it can significantly improve the pharmacological profile of the drug. A large number of 1,2,4-triazole derivatives are reported to possess a wide range of bioactivities including anti-cancer activity. This review article describes the role of 1,2,4-triazole nucleus in different types of anti-cancer agents such as nucleoside based anti-cancer agents, kinase inhibitors, tubulin modulators, aromatase and steroid sulfatase inhibitors, methionine aminopeptidase inhibitors, tankyrase inhibitors and metal complex based anti-cancer agents. It is expected that the current review article will provide insight into various ligand-receptor interactions and help in the rational design and development of novel 1,2,4-triazole based anti-cancer drugs with improved selectivity for cancer cells. ? 2016 Bentham Science Publishers.
Recent developments on the structure–activity relationship studies of MAO inhibitors and their role in different neurological disorders
(Royal Society of Chemistry, 2016) Kumar, Bhupinder; Sheetal; Mantha, Anil K.; Kumar, Vinod
Monoamine oxidase (MAO) enzyme catalyzes the oxidative deamination of xenobiotic and endogenous amines including many neurotransmitters. The MAO enzyme exists in two isoforms; MAO-A and MAO-B and these isoforms display considerable sequence similarity but differ in tissue distribution, inhibitor selectivity and specificity towards ligands. The altered concentration of the neurotransmitters in the brain is linked with the biochemical pathology of various neurological disorders including depression, Alzheimer's disease and Parkinson's disease. MAO inhibitors were the first antidepressants discovered but their irreversible binding to the enzyme resulted in a number of side effects including fatal food–drug interactions. The new generation MAO inhibitors, especially reversible and selective inhibitors, were less toxic and found to be effective against various neurological disorders. Now the MAO enzyme has been recognised as an important drug target and MAO-A selective inhibitors are being developed as drug candidates for the management of depression and anxiety disorders, whereas MAO-B selective inhibitors are found to be effective for the treatment of Parkinson's disease and Alzheimer's disease with a better safety profile as compared to nonselective MAO inhibitors. The current review article describes recent developments on the design, synthesis and screening of MAO inhibitors, structure–activity relationship studies, and their role in the etiology and treatment of various neurological disorders.
Regioselective alkylation of 1,2,4-triazole using ionic liquids under microwave conditions
(Walter de Gruyter GmbH, 2016) Kaur,Ramandeep; Kumar, Bhupinder; Dwivedi, Ashish Ranjan; Kumar, Vinod
1-Substituted 1,2,4-triazole derivatives present in a large number of compounds and display a variety of bioactivities such as antibiotic, anti-inflammatory, anti-diabetic, antipsychotic, and anticancer. A regioselective protocol has been developed for the alkylation of 1,2,4- triazole using mild conditions. The 1-alkyl-1,2,4-triazole derivatives were synthesized under microwave conditions using potassium carbonate as a base and ionic liquid (hexylpyridinium bromide) as a solvent. The products were obtained in excellent yield, and the base-ionic liquid combination was recycled for a number of times. ? 2016 by De Gruyter 2016.
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, Vinod
Neurological 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.
Role of peroxisome proliferator-activated receptor gamma (Ppar?) in different disease states: Recent updates
(Bentham Science Publishers, 2020-07-17T00:00:00) Mal, Suvadeep; Dwivedi, Ashish Ranjan; Kumar, Vijay; Kumar, Naveen; Kumar, Bhupinder; Kumar, Vinod
Peroxisome proliferator-activated receptor (PPAR), a ligand dependant transcription factor, is a member of the nuclear receptor superfamily. PPAR exists in three isoforms i.e. PPAR alpha (PPAR?), PPAR beta (PPAR?), and PPAR gamma (PPAR?). These are multi-functional transcription factors and help in regulating inflammation, type 2 diabetes, lipid concentration in the body, metastasis, and tumor growth or angiogenesis. Activation of PPAR? causes inhibition of growth of cultured human breast, gastric, lung, prostate, and other cancer cells. PPAR? is mainly involved in fatty acid storage, glucose metabolism, and homeo-stasis and adipogenesis regulation. A large number of natural and synthetic ligands bind to PPAR? and modulate its activity. Ligands such as thiazolidinedione troglitazone, rosiglita-zone, pioglitazone effectively bind to PPAR?; however, most of these were found to display severe side effects such as hepatotoxicity, weight gain, cardiovascular complications and bladder tumor. Now the focus is shifted towards the development of dual-acting or pan PPAR ligands. The current review article describes the functions and role of PPAR? in various disease states. In addition, recently reported PPAR? ligands and pan PPAR ligands were dis-cussed in detail. It is envisaged that the present review article may help in the development of potent PPAR ligands with no or minimal side effects. � 2021 Bentham Science Publishers.
Synthesis and biological evaluation of pyrimidine bridged combretastatin derivatives as potential anticancer agents and mechanistic studies
(Academic Press Inc., 2018) Kumar, Bhupinder; Sharma, Praveen; Gupta, Vivek Prakash; Khullar, Madhu; Singh, Sandeep; Dogra, Nilambra; Kumar, Vinod
A number of pyrimidine bridged combretastatin derivatives were designed, synthesized and evaluated for anticancer activities against breast cancer (MCF-7) and lung cancer (A549) cell lines using MTT assays. Most of the synthesized compounds displayed good anticancer activity with IC50 values in low micro-molar range. Compounds 4a and 4p were found most potent in the series with IC50 values of 4.67 ?M & 3.38 ?M and 4.63 ?M & 3.71 ?M against MCF7 and A549 cancer cell lines, respectively. Biological evaluation of these compounds showed that selective cancer cell toxicity (in vitro using human lung and breast cancer cell lines) might be due to the inhibition of antioxidant enzymes instigating elevated ROS levels which triggers intrinsic apoptotic pathways. These compounds were found nontoxic to the normal human primary cells. Compound 4a, was found to be competitive inhibitor of colchicine and in the tubulin binding assay it showed tubulin polymerization inhibition potential comparable to colchicine. The molecular modeling studies also showed that the synthesized compounds fit well in the colchicine-binding pocket. ? 2018 Elsevier Inc.
Synthesis, biological evaluation and molecular modeling studies of phenyl-/benzhydrylpiperazine derivatives as potential MAO inhibitors.
(Elsevier, 2018) Kumar, Bhupinder; Sheetal; Mantha, Anil K.; Kumar, Vinod
Monoamine oxidase inhibitors (MAOIs) are potential drug candidates for the treatment of various neurological disorders like Parkinson's disease, Alzheimer's disease and depression. In the present study, two series of 4-substituted phenylpiperazine and 1-benzhydrylpiperazine (1-21) derivatives were synthesized and screened for their MAO-A and MAO-B inhibitory activity using Amplex Red assay. Most of the synthesized compounds were found selective for MAO-B isoform except compounds 3, 7, 8, 9 and 13 (MAO-A selective) while compound 11 was non-selective. In the current series, compound 12 showed most potent MAO-B inhibitor activity with IC50 value of 80 nM and compound 7 was found to be most potent MAO-A inhibitor with IC50 value of 120 nM and both the compounds were found reversible inhibitors. Compound 8 was found most selective MAO-A inhibitor while compound 20 was found most selective inhibitor for MAO-B isoform. In the cytotoxicity evaluation, all the compounds were found non-toxic to SH-SY5Y and IMR-32 cells at 25 µM concentration. In the ROS studies, compound 8 (MAO-A inhibitor) reduced the ROS level by 51.2% while compound 13 reduced the ROS level by 61.81%. In the molecular dynamic simulation studies for 30 ns, compound 12 was found quite stable in the active cavity of MAO-B. Thus, it can be concluded that phenyl- and 1-benzhydrylpiperazine derivatives are promising MAO inhibitors and can act as a lead to design potent, and selective MAO inhibitors for the treatment of various neurological disorders.
Synthesis, biological evaluation and molecular modeling studies of phenyl-/benzhydrylpiperazine derivatives as potential MAO inhibitors
(Academic Press Inc., 2018) Kumar, Bhupinder; Sheetal; Mantha, Anil K.; Kumar, Vinod
Monoamine oxidase inhibitors (MAOIs) are potential drug candidates for the treatment of various neurological disorders like Parkinson's disease, Alzheimer's disease and depression. In the present study, two series of 4-substituted phenylpiperazine and 1-benzhydrylpiperazine (1?21) derivatives were synthesized and screened for their MAO-A and MAO-B inhibitory activity using Amplex Red assay. Most of the synthesized compounds were found selective for MAO-B isoform except compounds 3, 7, 8, 9 and 13 (MAO-A selective) while compound 11 was non-selective. In the current series, compound 12 showed most potent MAO-B inhibitor activity with IC50 value of 80 nM and compound 7 was found to be most potent MAO-A inhibitor with IC50 value of 120 nM and both the compounds were found reversible inhibitors. Compound 8 was found most selective MAO-A inhibitor while compound 20 was found most selective inhibitor for MAO-B isoform. In the cytotoxicity evaluation, all the compounds were found non-toxic to SH-SY5Y and IMR-32 cells at 25 ?M concentration. In the ROS studies, compound 8 (MAO-A inhibitor) reduced the ROS level by 51.2% while compound 13 reduced the ROS level by 61.81%. In the molecular dynamic simulation studies for 30 ns, compound 12 was found quite stable in the active cavity of MAO-B. Thus, it can be concluded that phenyl- and 1-benzhydrylpiperazine derivatives are promising MAO inhibitors and can act as a lead to design potent, and selective MAO inhibitors for the treatment of various neurological disorders. ? 2018 Elsevier Inc.
Synthesis, Biological Evaluation and Molecular Modeling Studies of Propargyl‐Containing 2,4,6‐Trisubstituted Pyrimidine Derivatives as Potential Anti‐Parkinson Agents
(Wiley, 2018) Kumar, Bhupinder; Kumar, Mohit; Dwivedi, Ashish Ranjan; Kumar, Vinod
Monoamine oxidase B (MAO‐B) inhibitors are potential drug candidates for the treatment of various neurological disorders including Parkinson's disease. A total of 20 new propargyl‐containing 2,4,6‐trisubstituted pyrimidine derivatives were synthesized and screened for MAO inhibition using Amplex Red assays. All the synthesized compounds were found to be reversible and selective inhibitors of the MAO‐B isoform at sub‐micromolar concentrations. MVB3 was the most potent MAO‐B inhibitor with an IC50 value of 0.38±0.02 μμ, whereas MVB6 (IC50=0.51±0.04 μμ) and MVB16 (IC50=0.48±0.06 μμ) were the most selective for MAO‐B with a selectivity index of more than 100‐fold. In cytotoxic studies, these compounds were found to be nontoxic to human neuroblastoma SH‐SY5Y cells at concentrations of 25 μm. MVB6 was found to decrease the intracellular level of reactive oxygen species to 68 % at 10 μm concentration, whereas other compounds did not produce significant changes in reactive oxygen species levels. In molecular modeling studies, MVB3 displayed strong binding affinity for the MAO‐B isoform with a dock score of −10.45, in agreement with the observed activity. All the compounds fitted well in the hydrophobic cavity of MAO‐B. Thus, propargyl‐substituted pyrimidine derivatives can be promising leads in the development of potent, selective and reversible MAO‐B inhibitors for the treatment of Parkinson's disease.