Novel Dipeptides Bearing Sulfonamide as Antimalarial and Antitrypanosomal agents: Synthesis and Molecular Docking

2021 ◽  
Vol 17 ◽  
Author(s):  
Ogechi Chinelo Ekoh ◽  
Uchechukwu Okoro ◽  
David Ugwu ◽  
Rafat Ali ◽  
Sunday Okafor ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Condensation Reaction ◽  
Drug Resistant ◽  
Protozoan Parasites ◽  
Diminazene Aceturate ◽  
Standard Drug ◽  
Tropical Regions ◽  
Haematological Analysis ◽  
New Compounds

Objective: Currently, there is a problem of ineffective chemotherapy to trypanosomiasis and the increasing emergence of malarial drug-resistant parasites. This research aimed to develop new dipeptide-sulfonamides as antiprotozoal agents. Background: Protozoan parasites cause severe diseases, with human African trypanosomaisis (HAT) and malaria leading the list. The noted deficiencies of existing antitrypanosomal drugs and the worldwide resurgence of malaria, accompanied by the springing up of widespread drug-resistant protozoan parasites, represent a huge challenge in infectious disease treatment in tropical regions. Methods: In order to discover new antiprotozoal agents, ten novel p-nitrobenzenesulphonamide derivatives incorporating dipeptide moiety were synthesized by the condensation reaction of 3-methyl-2-(4-nitrophenylsulphonamido)pentanoic acid (6) with substituted acetamides (4a-j) using peptide coupling reagents, characterized using 1H and 13C NMR, FTIR, HRMS, and investigated for their antimalarial and antitrypanosomal activities in vivo employing standard methods. Results: At 100 mg/kg body weight, N-(2-(2,6-dimethylphenylamino)-2-oxoethyl)-3-methyl-2-(4-nitrophenylsulfonamido)pentanamide showed the highest activity by inhibiting P. berghei parasite by 79.89%, which was comparable with the standard drug (artemether-lumefantrine 79.77%). In the antitrypanosomal study, N-(2-(4-chlorophenylamino)-2-oxoethyl)-3-methyl-2-(4-nitrophenylsulfonamido)pentanamide, N-(2-(4-fluorophenylamino)-2-oxoethyl)-3-methyl-2-(4-nitrophenylsulfonamido)pentanamide, and N-(2-(3-chlorophenylamino)-2-oxoethyl)-3-methyl-2-(4-nitrophenylsulfonamido)pentanamide were most potent in clearing Trypanosome brucei in mice. However, they were less active than the standard drug (diminazene aceturate). Molecular docking results demonstrated good binding affinity among the reported derivatives and target proteins in the active place of the protein. The outcome of haematological analysis and liver and kidney function tests showed that the new compounds had no adverse effect on the blood and organs. Conclusions: The results of this research showed that the new compounds demonstrated interesting antitrypanosomal and antimalarial potentials. However, further research should be carried out on the synthesized derivatives as promising drug candidates for trypanosomiasis and malaria.

Design, Synthesis, Characterization and in silico molecular docking studies and in vivo anti-inflammatory Activity of Pyrazoline clubbed Thiazolinone Derivatives

2020 ◽  
Vol 17 ◽  
Author(s):  
Deepak Kumar Singh ◽  
Mayank Kulshreshtha ◽  
Yogesh Kumar ◽  
Pooja A Chawla ◽  
Akash Ved ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Biological Activities ◽  
Inflammatory Activity ◽  
Standard Drug ◽  
Docking Score ◽  
Chemical Structures ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 1

Background: The pyrazolines give the reactions of aliphatic derivatives, resembling unsaturated compounds in their behavior towards permanganate and nascent hydrogen. This nucleus has been associated with various biological activities including inflammatory. Thiazolinone is a heterocyclic compound that contains both sulfur and nitrogen atom with a carbonyl group in their structure.Thiazolinone and their derivatives have attracted continuing interest because of their various biological activities, such as anti-inflammatory, antimicrobial, anti-proliferative, antiviral, anticonvulsant etc. The aim of the research was to club pyrazoline nucleus with thiazolinone in order to have significantanti-inflammatory activity. The synthesized compounds were chemically characterized for the establishment of their chemical structures and to evaluate as anti-inflammatory agent. Method: In the present work, eight derivatives of substituted pyrazoline (PT1-PT8) were synthesized by a three step reaction.The compounds were subjected to spectral analysis by Infrared, Mass and Nuclear magnetic resonance spectroscopy and elemental analysis data. All the synthesized were evaluated for their in vivo anti-inflammatory activity. The synthesized derivatives were evaluated for their affinity towards target COX-1 and COX-2, using indomethacin as the reference compound molecular docking visualization through AutoDock Vina. Results: Compounds PT-1, PT-3, PT-4 and PT-8 exhibited significant anti-inflammatory activity at 3rd hour being 50.7%, 54.3%, 52.3% and 57% respectively closer to that of the standard drug indomethacin (61.9%).From selected anti-inflammatory targets, the synthesized derivatives exhibited better interaction with COX-1 and COX-2 receptor, where indomethacin showed docking score of -6.5 kJ/mol, compound PT-1 exhibited highest docking score of -9.1 kJ/mol for COX-1 and compound PT-8 having docking score of 9.4 kJ/mol for COX-2. Conclusion: It was concluded that synthesized derivatives have more interaction with COX-2 receptors in comparison to the COX-1 receptors because the docking score with COX-2 receptors were very good. It is concluded that the synthesized derivatives (PT-1 to PT-8) are potent COX-2 inhibitors.

scholarly journals Derivatives of 2-Aminopyridines as Inhibitors of Multidrug Resistant Staphylococcus Aureus Strains

2018 ◽  
Vol 10 (1) ◽  
pp. 153
Author(s):  
Iniobong E. Ante ◽  
Sherifat A Aboaba ◽  
Hina Siddiqui ◽  
Muhammad A Bashir ◽  
Muhammad I Choudhary
Keyword(s):  
Staphylococcus Aureus ◽  
Mass Spectra ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Acid Chlorides ◽  
Alamar Blue ◽  
Standard Drug ◽  
Starting Point ◽  
New Compounds ◽  
Derivatives Of

A new series of 2-aminopyridine derivatives were synthesised. N-acylation of 2-amino-3-chloro-5-(trifluoromethyl) pyridine and 2-amino-5-(trifluoromethyl) pyridine with series of acid chlorides afforded a total of fourteen (14) amide compounds. The structures of the new compounds have been established by their IR, NMR and mass spectra data. All the compounds were tested for their activity against four (4) multi-drug resistant (MDR) bacteria Staphylococcus aureus strains using microplate alamar blue assay. The MDR-Staphylococcus aureus strains employed for this study were Epidermic Methicilin Resistant Staphylococcus aureus (EMRSA-17), Methicilin Resistant Staphylococcus aureus (MRSA-252), Epidermic Methicilin Resistant Staphylococcus aureus (EMRSA-16) and Pakistani Drug resistant clinical isolate of Staphylococcus aureus (PRSA). Other bacteria strains also used include Escherichia coli (ATCC 2592), Shigella flexenari (ATCC 12022), Staphylococcus aureus (NCTC 6571) and Pseudomonas aeruginosa (NCTC 10662). The synthesised compounds exhibited very good activity against the four MDR-Staphylococcus aureus strains of which most of the compounds showed higher potencies for inhibiting the growth of the strains than vancomycin, the standard drug employed. The compounds reported here may serve as the starting point for the design and development of MDR-S.aureus inhibitors as antibacterial agents.

scholarly journals In-silico Molecular Docking and ADME/Pharmacokinetic Prediction Studies of Some Novel Carboxamide Derivatives as Anti-tubercular Agents

2020 ◽  
Vol 3 (4) ◽  
pp. 989-1000
Author(s):  
Mustapha Abdullahi ◽  
Shola Elijah Adeniji
Keyword(s):  
Molecular Docking ◽  
Binding Affinity ◽  
In Silico ◽  
Density Functional ◽  
Docking Simulation ◽  
Basis Set ◽  
Hybrid Functional ◽  
Standard Drug

AbstractMolecular docking simulation of thirty-five (35) molecules of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamide (IPA) with Mycobacterium tuberculosis target (DNA gyrase) was carried out so as to evaluate their theoretical binding affinities. The chemical structure of the molecules was accurately drawn using ChemDraw Ultra software, then optimized at density functional theory (DFT) using Becke’s three-parameter Lee–Yang–Parr hybrid functional (B3LYP/6-311**) basis set in a vacuum of Spartan 14 software. Subsequently, the docking operation was carried out using PyRx virtual screening software. Molecule 35 (M35) with the highest binding affinity of − 7.2 kcal/mol was selected as the lead molecule for structural modification which led to the development of four (4) newly hypothetical molecules D1, D2, D3 and D4. In addition, the D4 molecule with the highest binding affinity value of − 9.4 kcal/mol formed more H-bond interactions signifying better orientation of the ligand in the binding site compared to M35 and isoniazid standard drug. In-silico ADME and drug-likeness prediction of the molecules showed good pharmacokinetic properties having high gastrointestinal absorption, orally bioavailable, and less toxic. The outcome of the present research strengthens the relevance of these compounds as promising lead candidates for the treatment of multidrug-resistant tuberculosis which could help the medicinal chemists and pharmaceutical professionals in further designing and synthesis of more potent drug candidates. Moreover, the research also encouraged the in vivo and in vitro evaluation study for the proposed designed compounds to validate the computational findings.

Thiazolidine-2, 4-Diones as Non-Hepatotoxic Tri-action Drug Candidates: Design, Synthesis, Characterization, Biological Evaluation and Docking Studies

2020 ◽  
Vol 17 (9) ◽  
pp. 659-679
Author(s):  
Karuna S. Shukla ◽  
Shailendra Pandey ◽  
Pooja A. Chawla
Keyword(s):  
Antioxidant Activity ◽  
Molecular Docking ◽  
Benzoic Acid ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Standard Drug ◽  
Peripheral Tissues ◽  
Docking Score ◽  
Dpph Method

Thiazolidine-2, 4-diones and their derivatives are a well-established chemical class of compounds that express their pharmacological actions through insulin sensitization and enhanced glucose utilization in peripheral tissues. In the current research different approaches have been employed to synthesize thiazolidine-2, 4-dione derivatives and these synthesized compounds were chemically characterized for the establishment of their chemical structures. A series of thiazolidine-2, 4-dione (TZD) derivatives, Scheme 1 (3A-3V) 22 compounds, were synthesized and characterized by FT-IR, 1H NMR and mass spectral analysis. The title compounds were screened for their in vitro and in vivo antidiabetic, antioxidant, and cytotoxicity studies. In vivo antihyperglycemic effect was assessed by measuring plasma glucose (PG) levels in alloxan-induced type II diabetic rat models. The synthesized TZD derivatives were evaluated for hepatotoxicity and pancreatic tissue integrity. Antioxidant activity was evaluated by the DPPH method and H2O2 method. Thiazolidinedione derivatives were subjected to predict free energy of binding towards target PPARγ, using rosiglitazone as the reference compound for molecular docking visualization through the FlexX docking program. Molecular docking studies are also performed for understanding the binding of a ligand to a receptor. The compound 3V 4-(5- (naphthalen-1-ylmethylene)-2, 4-dioxothiazolidin-3-yl) benzoic acid exhibited better blood glucoselowering activity than that of the standard drug rosiglitazone. Compound 3T and 3U exhibited potent antioxidant activity. Among the tested compounds for cytotoxicity using an MTT assay, compound 3H 5-(4-chlorobenzylidene)-2, 4-dioxothiazolidin-3-yl) benzoic acid exhibited better viability and cytotoxicity activity. From selected anti-diabetic targets, the proposed derivatives exhibited better interaction with PPARγ receptor, for example, while rosiglitazone showed a docking score of -19.891 kJ/mol, compound 3V exhibited highest docking score of -31.6617 kJ/mol. Computational molecular docking study demonstrated the selectivity and provided a binding model for the further refinement of this chemotype. Therefore, this series of thiazolidine-2, 4-diones derivatives (3A-3V) have considerable importance for development as a potential antihyperglycemic and hypolipidemic agents.

scholarly journals Predicting the bioactivity of 2-alkoxycarbonylallyl esters as potential antiproliferative agents against pancreatic cancer (MiaPaCa-2) cell lines: GFA-based QSAR and ELM-based models with molecular docking

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Oluwatoba Emmanuel Oyeneyin ◽  
Babatunde Samuel Obadawo ◽  
Adesoji Alani Olanrewaju ◽  
Taoreed Olakunle Owolabi ◽  
Fahidat Adedamola Gbadamosi ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Three Dimensional ◽  
Growth Factor Receptor ◽  
Qsar Model ◽  
Quantitative Structure Activity Relationship ◽  
Binding Energies ◽  
Standard Drug ◽  
Lead Compounds ◽  
Learning Machine ◽  
New Compounds

Abstract Background The number of cancer-related deaths is on the increase, combating this deadly disease has proved difficult owing to resistance and some serious side effects associated with drugs used to combat it. Therefore, scientists continue to probe into the mechanism of action of cancer cells and designing novel drugs that could combat this disease more safely and effectively. Here, we developed a genetic function approximation model to predict the bioactivity of some 2-alkoxyecarbonyl esters and probed into the mode of interaction of these molecules with an epidermal growth factor receptor (3POZ) using the three-dimensional quantitative structure activity relationship (QSAR), extreme learning machine (ELM), and molecular docking techniques. Results The developed QSAR model with predicted (R2pred) of 0.756 showed that the model was fit to be validated parameter for a built model and also proved that the developed model could be used in practical situation, R2 for training set (0.9929) and test set (0.8397) confirmed that the model could successfully predict the activity of new compounds due to its correlation with the experimental activity, the models generated with ELM models showed improved prediction of the activity of the molecules. The lead compounds (22 and 23) had binding energies of −6.327 and −7.232 kcalmol−1 for 22 and 23 respectively and displayed better inhibition at the binding sites of 3POZ when compared with that of the standard drug, chlorambucil (−6.0 kcalmol−1). This could be attributed to the presence of double bonds and the α-ester groups. Conclusion The QSAR and ELM models had good prognostic ability and could be used to predict the bioactivity of novel anti-proliferative drugs.

scholarly journals Homology modeling and molecular docking simulation of some novel imidazo[1,2-a]pyridine-3-carboxamide (IPA) series as inhibitors of Mycobacterium tuberculosis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Mustapha Abdullahi ◽  
Shola Elijah Adeniji ◽  
David Ebuka Arthur ◽  
Abdurrashid Haruna
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Homology Modeling ◽  
Binding Affinity ◽  
Docking Simulation ◽  
Computational Method ◽  
Multiple Drug ◽  
Drug Resistant ◽  
Standard Drug ◽  
Molecular Docking Simulation

Abstract Background Tuberculosis (TB) remains a serious global health challenge that is caused by Mycobacterium tuberculosis and has killed numerous people. This necessitated the urgent need for the hunt and development of more potent drugs against the fast-emerging extensively drug-resistant (XDR) and multiple-drug-resistant (MDR) M. tuberculosis strains. Mycobacterium tuberculosis cytochrome b subunit of the cytochrome bc1 complex (QcrB) was recognized as a potential drug target in M. tuberculosis (25618/H37Rv) for imidazo[1,2-a]pyridine-3-carboxamides whose crystal strucuture is not yet reported in the Protein Data Bank (PDB). The concept of homology modeling as a powerful and useful computational method can be applied, since the M. tuberculosis QcrB protein sequence data are available. Results The homology model of QcrB protein in M. tuberculosis was built from the X-ray structure of QcrB in M. smegmatis as a template using the Swiss-Model online workspace. The modeled protein was assessed, validated, and prepared for the molecular docking simulation of 35 ligands of N-(2-phenoxy)ethyl imidazo[1,2-a] pyridine-3-carboxamide (IPA) to analyze their theoretical binding affinities and modes. The docking results showed that the binding affinity values ranged from − 6.5 to − 10.1 kcal/mol which confirms their resilience potency when compared with 6.0kcal/mol of isoniazid standard drug. However, ligands 2, 7, 22, 26, and 35 scored higher binding affinity values of − 9.60, − 9.80, − 10.10, − 10.00, and − 10.00 kcal/mol, and are respectively considered as the best ligands among others with better binding modes in the active site of the modeled QcrB protein. Conclusion The information derived in this research revealed some potential hits and paved a route for structure-based drug discovery of new hypothetical imidazo pyridine amide analogs as anti-tubercular drug candidates.

scholarly journals Design, Synthesis, and Acute Anti-inflammatory Assessment of New 2-methyl Benzoimidazole Derivatives Having 4-Thiazolidinone Nucleus

2019 ◽  
pp. 151-160
Keyword(s):  
Molecular Docking ◽  
Control Group ◽  
Design Synthesis ◽  
Reference Drug ◽  
Reference Ligand ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
New Compounds ◽  
Cox 2 Inhibitors

New two derivatives of 2- methyl benzoimidazole were designed, synthesized and evaluated as a potential cyclooxygenase-2 [COX-2] inhibitors. The synthesized compounds have been recognized according to their spectral FT-IR, 1H-NMR data and physical pro- perties. The newly synthesized compounds were investigated in vivo for their anti-inflammatory activities using egg-white stimulated paw edema method with respect to the effect of propylene glycol 50%v/v [control group] and the ibuprofen [10mg/kg i.p.] was selected as a reference ligand. New compounds showed a significantly higher in vivo anti-inflammatory activity compared with ibuprofen as a reference drug. COX-2 selectivity evaluation through molecular docking via GOLD suite [v. 5.6.2.]. The new compounds via molecular docking showed significant higher activities when compared with ibuprofen as referenced drugs because of having hydrogen bonding interaction toward the key amino acids within COX-2 structure and all these results were compatible with the study of in vivo acute anti-inflammatory activities for tested compounds. ADME studies were performed to predict absorption, bioavailability, topological polar surface area, and drug-likeness. The results of ADME studies showed that all synthesized compounds absorbed from the gastrointestinal tract.

scholarly journals Synthesis, Molecular Docking Analysis and in Vitro Biological Evaluation of Some New Heterocyclic Scaffolds-Based Indole Moiety as Possible Antimicrobial Agents

2022 ◽  
Vol 8 ◽  
Author(s):  
Entesar A. Hassan ◽  
Ihsan A. Shehadi ◽  
Awatef M. Elmaghraby ◽  
Hadir M. Mostafa ◽  
Salem E. Zayed ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Antimicrobial Agents ◽  
Antibacterial Activities ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Standard Drug ◽  
Docking Analysis ◽  
Excellent Activity ◽  
New Compounds

In the present study, a general approach for the synthesis of 1-(1H-indol-3-yl)-3,3-dimercaptoprop-2-en-1-one (1) and 5-(1H-indol-3-yl)-3H-1,2-dithiole-3-thione (2) was performed. They are currently used as efficient precursors for the synthesis of some new compounds bearing five- and/or six-membered heterocyclic moieties, e.g., chromenol (3, 4), 3,4-dihydroquinoline (7, 8) and thiopyran (10, 12)-based indole core. In addition, molecular docking studies were achieved, which showed that all the newly synthesized compounds are interacting with the active site region of the target enzymes, the targets UDP-N-acetylmuramatel-alanine ligase (MurC), and human lanosterol14α-demethylase, through hydrogen bonds and pi-stacked interactions. Among these docked ligand molecules, the compound (9) was found to have the minimum binding energy (−11.5 and −8.5 Kcal/mol) as compared to the standard drug ampicillin (−8.0 and −8.1 Kcal/mol) against the target enzymes UDP-N-acetylmuramatel-alanine ligase (MurC), and Human lanosterol14α-demethylase, respectively. Subsequently, all new synthesized analogues were screened for their antibacterial activities against Gram-positive (Bacillus subtilis), and Gram-negative bacteria (Escherichia coli), as well as for antifungal activities against Candida albicans and Aspergillus flavus. The obtained data suggest that the compounds exhibited good to excellent activity against bacterial and fungi strains. The compound (E)-2-(6-(1H-indole-3-carbonyl)-5-thioxotetrahydrothieno [3,2-b]furan-2(3H)-ylidene)-3-(1H-indol-3-yl)-3-oxopropanedithioic acid (9) showed a high binding affinity as well as an excellent biological activity. Therefore, it could serve as the lead for further optimization and to arrive at potential antimicrobial agent.

scholarly journals Natural Occurrence in Venomous Arthropods of Antimicrobial Peptides Active against Protozoan Parasites

Toxins ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 563 ◽  
Author(s):  
Elias Ferreira Sabiá Júnior ◽  
Luis Felipe Santos Menezes ◽  
Israel Flor Silva de Araújo ◽  
Elisabeth Ferroni Schwartz
Keyword(s):  
Antimicrobial Peptides ◽  
Membrane Integrity ◽  
Complex Mixture ◽  
Host Immune System ◽  
Natural Occurrence ◽  
Protozoan Parasites ◽  
Tropical Regions ◽  
Wide Range ◽  
Life Threatening ◽  
New Compounds

Arthropoda is a phylum of invertebrates that has undergone remarkable evolutionary radiation, with a wide range of venomous animals. Arthropod venom is a complex mixture of molecules and a source of new compounds, including antimicrobial peptides (AMPs). Most AMPs affect membrane integrity and produce lethal pores in microorganisms, including protozoan pathogens, whereas others act on internal targets or by modulation of the host immune system. Protozoan parasites cause some serious life-threatening diseases among millions of people worldwide, mostly affecting the poorest in developing tropical regions. Humans can be infected with protozoan parasites belonging to the genera Trypanosoma, Leishmania, Plasmodium, and Toxoplasma, responsible for Chagas disease, human African trypanosomiasis, leishmaniasis, malaria, and toxoplasmosis. There is not yet any cure or vaccine for these illnesses, and the current antiprotozoal chemotherapeutic compounds are inefficient and toxic and have been in clinical use for decades, which increases drug resistance. In this review, we will present an overview of AMPs, the diverse modes of action of AMPs on protozoan targets, and the prospection of novel AMPs isolated from venomous arthropods with the potential to become novel clinical agents to treat protozoan-borne diseases.

In-vivo evaluation of lipid lowering ability of Chloris paraguaiensis extracts

2020 ◽  
Vol 7 (2) ◽  
pp. 21-24
Author(s):  
Pavani C H
Keyword(s):  
Medicinal Plants ◽  
Chemical Constituents ◽  
The Body ◽  
Lipid Lowering ◽  
Medical Systems ◽  
In Vivo Evaluation ◽  
Standard Drug ◽  
Anti Oxidant ◽  
And Control

Hyperlipidemia is the immediate results of the excessive fat intake in food. This results in the elevated levels of cholesterol and triglycerides in the blood. This leads to heart conditions like CAD, hypertension, congestive heart failure as risk factors which can be lethal. There are many drugs to treat and control the lipids levels in the body. These drugs are either designed to prevent LDL accumulation and VLDL synthesis. Some drugs also lower the elevated levels of saturated lipids in the body. But many drugs are known to cause side effects and adverse effects; therefore, alternatives to the drugs are the subjects for current investigations. Herbs and medicinal plants are used as treatment sources for many years. They have been used in the Indian medical systems like Ayurveda, Siddha etc. As the application of herbs in the treatment is growing, there is an urgent need for the establishment of Pharmacological reasoning and standardization of the activity of the medicinal plants. Chloris paraguaiensis Steud. is Poyaceae member that is called locally as Uppugaddi. Traditionally it is used to treat Rheumatism, Diabetes, fever and diarrhoea. The chemical constituents are known to have anti-oxidant properties and most of the anti-oxidants have anti-hyperlipidemic activity too. Since the plant has abundant flavonoid and phenol content, the current research focusses on the investigation of the anti-hyperlipidemic activity of the plant Chloris extracts. Extracts of Chloris at 200mg/kg showed a comparably similar anti hyperlipidemia activity to that of the standard drug. The extracts showed a dose based increase in the activity at 100 and 200mg/kg body weight.

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