Browsing by Author "Kumar, Vinod"

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3-D QSAR Study Of Combretastatins Fused With Hetrocyclic Ring As Tubulin Binding Agents
(Central University of Punjab, 2018) Dhanka, Ajit Kumar; Kumar, Vinod
Combretastatin A4 (CA4) is a leading agent in vascular disrupting strategies and tubulin polymerization inhibitor for the tumour therapy. A large number of combretastatin derivatives have been synthesized as potent inhibitors of Tubulin which are responsible for the anticancer activity. Combretastatins bind with the colchicine binding site of the tubulin and disrupt the dynamic equilibrium of tubulin. IN the current research proposal we have performed 3D-Field based QSAR on Combretastatins analogue in order to recognize structural features which are responsible for the tubulin inhibitors activity. The designed compounds are expected to show good inhibitory activity against tubulin when electrostatic group is attached in case of compounds 16 and 18, Bulky group is attached in case of compound 26 and hydrophobic group is attached in case of compound 51 respectively.
4,6-Diphenylpyrimidine Derivatives as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase for the Treatment of Alzheimer's Disease
(American Chemical Society, 2019) Kumar, B; Dwivedi, A.R; Sarkar, B; Gupta, S.K; Krishnamurthy, S; Mantha, Anil K; Parkash, Jyoti; Kumar, Vinod
Alzheimer's disease (AD) is a neurodegenerative disorder with multifactorial pathogenesis. Monoamine oxidase (MAO) and acetylcholinesterase enzymes (AChE) are potential targets for the treatment of AD. A total of 15 new propargyl containing 4,6-diphenylpyrimidine derivatives were synthesized and screened for the MAO and AChE inhibition activities along with ROS production inhibition and metal-chelation potential. All the synthesized compounds were found to be selective and potent inhibitors of MAO-A and AChE enzymes at nanomolar concentrations. VB1 was found to be the most potent MAO-A and BuChE inhibitor with IC 50 values of 18.34 ± 0.38 nM and 0.666 ± 0.03 μM, respectively. It also showed potent AChE inhibition with an IC 50 value of 30.46 ± 0.23 nM. Compound VB8 was found to be the most potent AChE inhibitor with an IC 50 value of 9.54 ± 0.07 nM and displayed an IC 50 value of 1010 ± 70.42 nM against the MAO-A isoform. In the cytotoxic studies, these compounds were found to be nontoxic to the human neuroblastoma SH-SY5Y cells even at 25 μM concentration. All the compounds were found to be reversible inhibitors of MAO-A and AChE enzymes. In addition, these compounds also showed good neuroprotective properties against 6-OHDA- and H 2 O 2 -induced neurotoxicity in SH-SY5Y cells. All the compounds accommodate nicely to the hydrophobic cavity of MAO-A and AChE enzymes. In the molecular dynamics simulation studies, both VB1 and VB8 were found to be stable in the respective cavities for 30 ns. Thus, 4,6-diphenylpyrimidine derivatives can act as promising leads in the development of dual-acting inhibitors targeting MAO-A and AChE enzymes for the treatment of Alzheimer's disease. © 2018 American Chemical Society.
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, Vinod
Alzheimer'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 Ltd
Benzotriazole Substituted 2-Phenylquinazolines as Anticancer Agents: Synthesis, Screening, Antiproliferative and Tubulin Polymerization Inhibition Activity
(Bentham Science Publishers, 2022-10-28T00:00:00) Dwivedi, Ashish Ranjan; Rawat, Suraj Singh; Kumar, Vijay; Kumar, Naveen; Kumar, Vinay; Yadav, Ravi Prakash; Baranwal, Somesh; Prasad, Amit; Kumar, Vinod
Aims: Development of anticancer agents targeting tubulin protein. Background: Tubulin protein is being explored as an important target for anticancer drug development. Ligands binding to the colchicine binding site of the tubulin protein act as tubulin polymerization inhibitors and arrest the cell cycle in the G2/M phase. Objective: Synthesis and screening of benzotriazole-substituted 2-phenyl quinazolines as potential anticancer agents. Methods: A series of benzotriazole-substituted quinazoline derivatives have been synthesized and evaluated against human MCF-7 (breast), HeLa (cervical) and HT-29 (colon) cancer cell lines using standard MTT assays. Results: ARV-2 with IC50 values of 3.16 �M, 5.31 �M, 10.6 �M against MCF-7, HELA and HT29 cell lines, respectively displayed the most potent antiproliferative activities in the series while all the compounds were found non-toxic against HEK293 (normal cells). In the mechanistic studies involving cell cycle analysis, apoptosis assay and JC-1 studies, ARV-2 and ARV-3 were found to induce mitochondria-mediated apoptosis. Conclusion: The benzotriazole-substituted 2-phenyl quinazolines have the potential to be developed as potent anticancer agents. � 2023 Bentham Science Publishers.
Benzotriazole Substituted 2-Phenylquinazolines as Anticancer Agents: Synthesis, Screening, Antiproliferative and Tubulin Polymerization Inhibition Activity
(Bentham Science Publishers, 2022-10-28T00:00:00) Dwivedi, Ashish Ranjan; Rawat, Suraj Singh; Kumar, Vijay; Kumar, Naveen; Kumar, Vinay; Yadav, Ravi Prakash; Baranwal, Somesh; Prasad, Amit; Kumar, Vinod
Aims: Development of anticancer agents targeting tubulin protein. Background: Tubulin protein is being explored as an important target for anticancer drug development. Ligands binding to the colchicine binding site of the tubulin protein act as tubulin polymerization inhibitors and arrest the cell cycle in the G2/M phase. Objective: Synthesis and screening of benzotriazole-substituted 2-phenyl quinazolines as potential anticancer agents. Methods: A series of benzotriazole-substituted quinazoline derivatives have been synthesized and evaluated against human MCF-7 (breast), HeLa (cervical) and HT-29 (colon) cancer cell lines using standard MTT assays. Results: ARV-2 with IC50 values of 3.16 �M, 5.31 �M, 10.6 �M against MCF-7, HELA and HT29 cell lines, respectively displayed the most potent antiproliferative activities in the series while all the compounds were found non-toxic against HEK293 (normal cells). In the mechanistic studies involving cell cycle analysis, apoptosis assay and JC-1 studies, ARV-2 and ARV-3 were found to induce mitochondria-mediated apoptosis. Conclusion: The benzotriazole-substituted 2-phenyl quinazolines have the potential to be developed as potent anticancer agents. � 2023 Bentham Science Publishers.
C7β-Methyl Analogues of the Orvinols: The Discovery of Kappa Opioid Antagonists with Nociceptin/Orphanin FQ Peptide (NOP) Receptor Partial Agonism and Low, or Zero, Efficacy at Mu Opioid Receptors
(ACS Publications, 2015) Cueva, Juan Pablo; Roche, Christopher; Ostovar, Mehrnoosh; Kumar, Vinod; Clark, Mary J.; Hillhouse, Todd M.; Lewis, John W.; Traynor, John R.; Husbands, Stephen M.
Buprenorphine is a successful analgesic and treatment for opioid abuse, with both activities relying on its partial agonist activity at mu opioid receptors. However, there is substantial interest in its activities at the kappa opioid and nociceptin/orphanin FQ peptide receptors. This has led to an interest in developing compounds with a buprenorphine-like pharmacological profile but with lower efficacy at mu opioid receptors. The present article describes aryl ring analogues of buprenorphine in which the standard C20-methyl group has been moved to the C7β position, resulting in ligands with the desired profile. In particular, moving the methyl group has resulted in far more robust kappa opioid antagonist activity than seen in the standard orvinol series. Of the compounds synthesized, a number, including 15a, have a profile of interest for the development of drug abuse relapse prevention therapies or antidepressants and others (e.g., 8c), as analgesics with a reduced side-effect profile.
Caesium carbonate promoted regioselective O-functionalization of 4,6-diphenylpyrimidin-2(1H)-ones under mild conditions and mechanistic insight
(Royal Society of Chemistry, 2023-06-05T00:00:00) Kumar, Vijay; Singh, Praval Pratap; Dwivedi, Ashish Ranjan; Kumar, Naveen; Rakesh kumar, None; Chandra Sahoo, Subash; Chakraborty, Sudip; Kumar, Vinod
A facile one-step catalyst free methodology has been developed for the regioselective functionalization of 4,6-diphenylpyrimidin-2(1H)-ones under mild conditions. Selectivity towards the O-regioisomer was achieved by using Cs2CO3 in DMF without use of any coupling reagents. A total of 14 regioselective O-alkylated 4,6-diphenylpyrimidines were synthesized in 81-91% yield. In the DFT studies it was observed that the transition state for the formation of the O-regioisomer is more favourable with Cs2CO3 as compared to K2CO3. Furthermore, this methodology was extended to increase the O/N ratio for the alkylation of 2-phenylquinazolin-4(3H)-one derivatives. � 2023 The Royal Society of Chemistry.
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
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, Rakesh
An 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.
Design and synethesis of putative anti-cancer agents using hybrid molecular approach
(Central University of Punjab, 2014) Saini, Vijayinder; Kumar, Vinod
A Hybrid drug involves the unification of two drug pharmacophores in one single molecule. The hybrid drugs are designed to interact with multiple targets or to intensify its effect through action on another bio target as one single molecule or to counterbalance the known side effects associated with the other hybrid part. One of the important role of hybrid drugs is to counter multidrug resistance. Muti-drug resistance observed during the treatment for cancer. Target therapy for various cancer are developed and successfully used to treat cancer patient. But treatment can be further strengthen by concurrent administration of single drug by combining two different drugs from different origin act at different receptor to cope MDR. It is also said as to load a multi-target drug in a single drug. In the current research proposal, we have designed and synthesized molecules which affect tubulin polymerization as well as MetAP-2 receptor. Both play vital role in tumor progression by strengthening the cell cytoskeleton and angiogenesis process respectively. The hybrids of chalcone (antitubulin) and arylazole (anti MetAP-2) were synthesized and molecular docking studies were performed. The compounds were synthesized by three step reaction and synthesized compounds were analyzed and confirmed by FTIR, NMR and mass spectrometry. The activity of synthesized compound was evaluated against HCT-116 (wild & null type) colon cancer cell lines at a concentration of 5 μM, 25 μM and 50 μM. Compounds were equally active in wild type and null type HTC-116 cell lines with slight less inhibition in null type. Lastly, the information on inhibitory potential of compounds v were obtained from MTT assay wherein VJ-4, VJ-2PP2 & VJ-4PP1 were found to be active anticancer agents
Design, synthesis and evaluation of 4-phenyl-1,2,3-triazole substituted pyrimidine derivatives as antiproliferative and tubulin polymerization inhibitors
(Elsevier B.V., 2022-06-26T00:00:00) Dwivedi, Ashish Ranjan; Kumar, Vijay; Yadav, Ravi Prakash; Kumar, Naveen; Jangid, Kailash; Anand, Piyush; Sharma, Deepak Kumar; Barnawal, Somesh; Kumar, Vinod
Ligands binding to the colchicine domain of the tubulin protein act as tubulin polymerization inhibitors and arrest the cell cycle in G2/M phase. A series of 4-Phenyl-1,2,3-triazole substituted pyrimidine derivatives have been synthesized and evaluated for antiproliferative and antitubulin activities. In the series, AV-6 and AV-14 were found to be active against the three tested cancer cell lines wherein AV-6 displayed IC50 values of 1.2 �M, 5.5 �M, and 1.9 �M while AV-14 displayed IC50 values of 4.7 �M, 1.7 �M, and 1.4 �M against HCT-116, MCF-7 and HT-29 cell lines, respectively. These compounds were found to be non toxic to the normal cells (HEK-293). In the cell cycle analysis and JC-1 studies, these compounds induce mitocondria mediated apoptosis. In the tubulin polymerization inhibition studies, AV-6 displayed significant tubulin polymerization inhibition potential. In the molecular docking and simulation studies, these compounds fit well in the active site of colchicine. � 2022 Elsevier B.V.
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 biological evaluation of N-[1-(6?-chloropyridazin-3?-yl)-3-(4?-substitutedphenyl)-1H-pyrazole-5-yl]alkanamides as anti-inflammatory agents
(John Wiley and Sons Inc, 2022-01-22T00:00:00) Aggarwal, Ranjana; Swati, S.; Kumar, Vinod; Singh, Randhir; Kajal, Anu; Saini, Deepika
A series of structurally diverse N-[1-(6?-chloropyridazin-3?-yl)-3-(4?-substitutedphenyl)-1H-pyrazole-5-yl]alkanamides 5(a�r) has been designed and synthesized via Aliquat 336 catalyzed amidation of 5-amino-3-aryl-1-(6?-chloropyridazin-3?-yl)pyrazoles 3(a�c). The target compounds were designed on basis of the results obtained from the study of Lipinski's rule of five and binding interactions with target protein 3LN1. Eventually, compounds 5(a�r) were screened for their in vitro anti-inflammatory action by using inhibition of albumin denaturation and membrane stabilization assay. It has been found that all the synthesized compounds obeyed Lipinski's rule of five (nviolations�=�0�1) and showed weak to strong binding interactions with dock score range ?8.0 to ?9.9�kcal/mol. All alkanamides exhibited moderate to excellent activity as compared to the standard drug, Aspirin. Interestingly, the results indicated that the compound 5a may act as a promising medicinal lead as an anti-inflammatory agent for in vivo and clinical testing in future. � 2022 Wiley Periodicals LLC.
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
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, Rakesh
An 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.
Genomic alterations associated with HER2+ breast cancer risk and clinical outcome in response to trastuzumab
(Springer, 2019) Singla, H; Kaur, R.P; Shafi, G; Vashistha, R; Banipal, R.P.S; Kumar, Vinod; Munshi, Anjana
Human epidermal growth factor receptor 2 positive (HER2+) breast cancer (BC) is an aggressive BC subtype characterized by HER2 overexpression/amplification. Genomic alterations of HER2 and others have been reported to be associated with, HER2 overexpression and prediction of trastuzumab-response. Here, we aimed at identifying germline and somatic alterations associated with HER2+ BC and evaluating their association with clinical outcome in response to trastuzumab therapy given to HER2+ BC patients. Global Sequencing Array (GSA) and polymerase chain reaction-restriction length polymorphism (PCR-RFLP) techniques were used to determine alterations in HER2 and other HER2-interacting as well as signaling-related genes in HER2+ BC. In addition, 20 formalin fixed paraffin-embedded tissue samples were also evaluated by GSA for identifying significant variations associated with HER + BC as well as response to trastuzumab therapy. A germline variant in HER2 (I655V) was found to be significantly associated with the risk of the disease (p < 0.01). A nonsense mutation in PTPN11 (K99X), a pathogenic CCND1 splice site variant (P241P), a hotspot missense mutation in PIK3CA (E542K) and a hotspot missense mutation in TP53 (R249S); were observed in 25%, 75%, 30% and 40% of the HER2+ BC tissue samples, respectively. Mutant CCND1 (P241P) and PIK3CA (E542K) were found to be significantly associated with reduced disease-free survival (DFS) in patients treated with trastuzumab (p: 0.018 and 0.005, respectively). These results indicate that HER2, PTPN11, CCND1 and PIK3CA genes are important biomarkers in HER2+ BC. Moreover, the patients harboring mutant CCND1 and PIK3CA exhibit a poorer clinical outcome as compared to those carrying wild-type CCND1 and PIK3CA. © 2018, Springer Nature B.V.
Identification of 1,3,4-oxadiazoles as tubulin-targeted anticancer agents: a combined field-based 3D-QSAR, pharmacophore model-based virtual screening, molecular docking, molecular dynamics simulation, and density functional theory calculation approach
(Taylor and Francis Ltd., 2023-09-11T00:00:00) Das, Agnidipta; Sarangi, Manaswini; Jangid, Kailash; Kumar, Vijay; Kumar, Amit; Singh, Praval Pratap; Kaur, Kamalpreet; Kumar, Vinod; Chakraborty, Sudip; Jaitak, Vikas
Cancer is one of the most prominent causes of death worldwide and tubulin is a crucial protein of cytoskeleton that maintains essential cellular functions including cell division as well as cell signalling, that makes an attractive drug target for cancer drug development. 1,3,4-oxadiazoles disrupt microtubule causing G2-M phase cell cycle arrest and provide anti-proliferative effect. In this study, field-based 3D-QSAR models were developed using 62 bioactive anti-tubulin 1,3,4-oxadiazoles. The best model characterized by PLS factor 7 was rigorously validated using various statistical parameters. Generated 3D-QSAR model having high degree of confidence showed favourable and unfavourable contours around 1,3,4-oxadiazole core that assisted in defining proper spatial positioning of desired functional groups for better bioactivity. A five featured pharmacophore model (AAHHR_1) was developed using same ligand library and validated through enrichment analysis (BEDROC160.9 value = 0.59, Average EF 1% = 27.05, and AUC = 0.74). Total 30,212 derivatives of 1,3,4-oxadiazole obtained from PubChem database was prefiltered through validated pharmacophore model and docked in XP mode on binding cavity of tubulin protein (PDB code: 1SA0) which led into the identification of 11 HITs having docking scores between ?7.530 and ?9.719 kcal/mol while the reference compound Colchicine exerted docking score of ?7.046 kcal/mol. Following the analysis of MM-GBSA and ADME studies, HIT1 and HIT4 emerged as the two promising hits. To verify their thermodynamic stability at the target site, molecular dynamic simulations were carried out. Both HITs were further subjected to DFT analysis to determine their HOMO-LUMO energy gap for ensuring their biological feasibility. Finally, molecular docking based structural exploration for 1,3,4-oxadiazoles to set up a lead of Formula I for further advancements of tubulin polymerization inhibitors as anti-cancer agents. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.
Identification of terpenoids as dihydropteroate synthase and dihydrofolate reductase inhibitors through structure-based virtual screening and molecular dynamic simulations
(Taylor and Francis Ltd., 2023-05-13T00:00:00) Saini, Abhishek; Kumar, Amit; Jangid, Kailash; Kumar, Vinod; Jaitak, Vikas
Bacterial infections are rising, and antimicrobial resistance (AMR) in bacteria has worsened the scenario, requiring extensive research to find alternative therapeutic agents. Terpenoids play an essential role in protecting plants from herbivores and pathogens. The present study was designed to focus on in silico evaluation of terpenoids for their affinity towards two necessary enzymes, i.e. DHFR and DHPS, which are involved in forming 5, 6, 7, 8-tetrahydrofolate, a key component in bacterial DNA synthesis proteins. Additionally, to account for activity against resistant bacteria, their affinity towards the L28R mutant of DHFR was also assessed in the study. The structure-based drug design approach was used to screen the compound library of terpenes for their interaction with active sites of DHFR and DHPS. Further, compounds were screened based on their dock score, pharmacokinetic properties, and binding affinities. A total of five compounds for each target protein were screened, having dock scores better than their respective standard drug molecules. CNP0169378 (?8.4 kcal/mol) and CNP0309455 (?6.5 kcal/mol) have been identified as molecules with a higher affinity toward the targets of DHFR and DHPS, respectively. At the same time, one molecule CNP0298407 (?5.8 kcal/mol for DHPS, ?7.6 kcal/mol for DHFR, ?6.1 kcal/mol for the L28R variant), has affinity for both proteins (6XG5 and 6XG4). All the molecules have good pharmacokinetic properties. We further validated the docking study by binding free energy calculations using the MM/GBSA approach and molecular dynamics simulations. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.
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