Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 8 de 8
Filter
Add more filters










Database
Language
Publication year range
1.
Chem Biol Interact ; 297: 34-43, 2019 Jan 05.
Article in English | MEDLINE | ID: mdl-30342014

ABSTRACT

A water-soluble curcumin lysinate incorporated into hydroxypropyl-ß-cyclodextrin (NDS27) has been developed and shown anti-inflammatory properties but no comparative study has been made in parallel with its parent molecule, curcumin on polymorphonuclear neutrophils (PMNs) and myeloperoxidase (MPO) involved in inflammation. The effect of NDS27, its excipients (hydroxypropyl-ß-cyclodextrin and lysine), curcumin lysinate and curcumin were compared on the release of superoxide anion by PMNs using a chemiluminescence assay and on the enzymatic activity of MPO. It was shown that curcumin and NDS27 exhibit similar inhibition activities on superoxide anion release by stimulated PMNs but also on MPO peroxidase and halogenation activities. The action mechanism of curcumin and NDS27 on the MPO activity was refined by stopped-flow and docking analyses. We demonstrate that both curcumin and NDS27 are reversible inhibitors of MPO by acting as excellent electron donors for redox intermediate Compound I (∼107 M-1 s-1) but not for Compound II (∼103 M-1 s-1) in the peroxidase cycle of the enzyme, thereby trapping the enzyme in the Compound II state. Docking calculations show that curcumin is able to enter the enzymatic pocket of MPO and bind to the heme cavity by π-stacking and formation of hydrogen bonds involving substituents from both aromatic rings. Hydroxypropyl-ß-cyclodextrin is too bulky to enter MPO channel leading to the binding site suggesting a full release of curcumin from the cyclodextrin thereby allowing its full access to the active site of MPO. In conclusion, the hydroxypropyl-ß-cyclodextrin of NDS27 enhances curcumin solubilization without affecting its antioxidant capacity and inhibitory activity on MPO.


Subject(s)
Antioxidants/pharmacology , Curcumin/pharmacology , Enzyme Inhibitors/pharmacology , Neutrophils/drug effects , Peroxidase/antagonists & inhibitors , Superoxides/antagonists & inhibitors , Animals , Anions/antagonists & inhibitors , Anions/metabolism , Antioxidants/chemistry , Curcumin/analogs & derivatives , Curcumin/chemistry , Enzyme Inhibitors/chemistry , Horses , Molecular Docking Simulation , Neutrophils/metabolism , Peroxidase/metabolism , Solubility , Superoxides/metabolism
2.
J Med Chem ; 60(15): 6563-6586, 2017 08 10.
Article in English | MEDLINE | ID: mdl-28671460

ABSTRACT

The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great interest in the development of new efficient and specific inhibitors. Here, we have performed a novel virtual screening procedure, depending on ligand-based pharmacophore modeling followed by structure-based virtual screening. Starting from a set of 727842 compounds, 28 molecules were selected by this virtual method and tested on MPO in vitro. Twelve out of 28 compounds were found to have an IC50 less than 5 µM. The best inhibitors were 2-(7-methoxy-4-methylquinazolin-2-yl)guanidine (28) and (R)-2-(1-((2,3-dihydro-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-5-fluoro-1H-benzo[d]imidazole (42) with IC50 values of 44 and 50 nM, respectively. Studies on the mechanism of inhibition suggest that 28 is the first potent mechanism-based inhibitor and inhibits irreversibly MPO at nanomolar concentration.


Subject(s)
Benzimidazoles/pharmacology , Enzyme Inhibitors/pharmacology , Guanidines/pharmacology , Peroxidase/antagonists & inhibitors , Quinazolines/pharmacology , Benzimidazoles/chemical synthesis , Benzimidazoles/toxicity , Cell Line , Databases, Chemical , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/toxicity , Glutamic Acid/chemistry , Glutamine/chemistry , Guanidines/chemical synthesis , Guanidines/toxicity , Humans , Hydrogen Peroxide/chemistry , Kinetics , Lactoperoxidase/antagonists & inhibitors , Lipoproteins, LDL/chemistry , Models, Chemical , Molecular Docking Simulation , Neutrophils/drug effects , Neutrophils/metabolism , Oxidation-Reduction , Quinazolines/chemical synthesis , Quinazolines/toxicity , Stereoisomerism
3.
Eur J Med Chem ; 123: 746-762, 2016 Nov 10.
Article in English | MEDLINE | ID: mdl-27537923

ABSTRACT

Human myeloperoxidase (MPO) plays an important role in innate immunity but also aggravates tissue damage by oxidation of biomolecules at sites of inflammation. As a result from a recent high-throughput virtual screening approach for MPO inhibitors, bis-2,2'-[(dihydro-1,3(2H,4H) pyrimidinediyl)bis(methylene)]phenol was detected as a promising lead compound for inhibition of the MPO-typical two-electron oxidation of chloride to hypochlorous acid (IC50 = 0.5 µM). In the present pharmacomodulation study, 37 derivatives of this lead compound were designed and synthesized driven by comprehensive docking studies and the impact on the chlorination activity of MPO. We describe the structural requirements for optimum (i) binding to the heme periphery and (ii) inhibition capacity. Finally, the best three inhibitors (bis-arylalkylamine derivatives) were probed for interaction with the MPO redox intermediates Compound I and Compound II. Determined apparent bimolecular rate constants together with determination of reduction potential and nucleophilicity of the selected compounds allowed us to propose a mechanism of inhibition. The best inhibitor was found to promote the accumulation of inactive form of MPO-Compound II and has IC50 = 54 nM, demonstrating the successful approach of the drug design. Due to the similarity of ligand interactions between MPO and serotonine transporter, the selectivity of this inhibitor was also tested on the serotonin transporter providing a selectivity index of 14 (KiSERT/IC50MPO).


Subject(s)
Amines/chemical synthesis , Amines/pharmacology , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Peroxidase/antagonists & inhibitors , Amines/chemistry , Amines/metabolism , Chemistry Techniques, Synthetic , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Halogenation , Humans , Kinetics , Molecular Docking Simulation , Oxidation-Reduction , Peroxidase/chemistry , Peroxidase/metabolism , Protein Conformation , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity Relationship
4.
Curr Med Chem ; 23(35): 3975-4008, 2016.
Article in English | MEDLINE | ID: mdl-27281130

ABSTRACT

Inflammation is an initial response of the body to a harmful stimuli and it is achieved by the increased movement of leukocytes (especially granulocytes) from blood into injured tissues. It is required for healing wounds and infections. Despite their indispensable role in microbial killing, the inflammation reactions may also cause diseases to a host such as hay fever, atherosclerosis, and rheumatoid arthritis. The enzymes and oxidizing species released during the inflammatory process can cause damages to the host tissues which lead to inflammatory syndromes. The role of myeloperoxidase (MPO) in the inflammatory reactions is well documented. It contributes in killing the pathogens but it is also implicated in several inflammatory syndromes such as Parkinson's disease, Alzheimer's disease and atherosclerosis. Thus, this enzyme has attracted more attention of the scientists and it has become a target for drug designing. In the last decade, several reversible and irreversible MPO inhibitors were identified as very high potent inhibitors such as fluoroalkylindole, aromatic hydroxamic acid, thioxanthine and benzoic acid hydrazide derivatives. In this review, we tried to illustrate the MPO inhibitors and highlight their structure activity relationship (SAR). In this paper we also discussed the mechanism of the inhibitory effect of the most potent compounds.


Subject(s)
Enzyme Inhibitors/chemistry , Peroxidase/metabolism , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/pathology , Atherosclerosis/drug therapy , Atherosclerosis/pathology , Chalcones/chemistry , Chalcones/metabolism , Chalcones/therapeutic use , Drug Design , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/therapeutic use , Flavonoids/chemistry , Flavonoids/metabolism , Flavonoids/therapeutic use , Humans , Molecular Docking Simulation , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/pathology , Peroxidase/antagonists & inhibitors , Structure-Activity Relationship
5.
J Ethnopharmacol ; 154(2): 361-9, 2014 Jun 11.
Article in English | MEDLINE | ID: mdl-24746482

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Seeds and aerial parts of Peganum harmala L. are widely used in Algeria as anti-inflammatory remedies. Evaluation of Peganum harmala total alkaloids extracts and pure ß-carboline compounds as an anti-inflammatory treatment by the inhibition of an enzyme key of inflammatory, myeloperoxidase (MPO) and HPLC quantification of the alkaloids from the different parts of plant. MATERIALS AND METHODS: MPO inhibition was tested using taurine chloramine test. The inhibition of LDL oxidation induced by MPO was carried out. The molecular docking analysis of Peganum harmala alkaloids on MPO was performed using the Glide XP docking protocol and scoring function and the redox potential of alkaloids was determined using an Epsilon potentiostat. The concentration of harmala alkaloids was determined using HPLC analysis. RESULTS: The HPLC profiling of the active total alkaloids indicates that ß-carboline e.g. harmine, harmaline, harmane, harmol and harmalol are major components. As ß-carbolines resemble tryptamine, of which derivatives are efficient inhibitors of MPO, the harmala alkaloids were tested for their activity on this enzyme. Total alkaloids of the seeds and of the aerial parts strongly inhibited MPO at 20µg/mL (97±5% and 43±4%, respectively) whereas, at the same concentration, those of the roots showed very low inhibition (15±6%). Harmine, harmaline and harmane demonstrated a significant inhibition of MPO at IC50 of 0.26, 0.08 and 0.72µM respectively. These alkaloids exerted a similar inhibition effects on MPO-induced LDL oxidation. Molecular docking analysis of Peganum harmala alkaloids on MPO showed that all active Peganum harmala alkaloids have a high affinity on the active site of MPO (predicted free energies of binding up to -3.1kcal/mol). Measurement of redox potentials versus the normal hydrogen electrode clearly differentiated (i) the high MPO inhibitory activity of harmine, harmaline and harmane (+1014, 1014 and 1003mV, respectively); and (ii) the low activity of harmalol and harmol (+629/778 and 532/644mV, respectively). A reverse phase HPLC method has been developed to determine simultaneously five alkaloids of Peganum harmala. Seeds contained all five ß-carboline derivatives with the main active alkaloids, harmaline and harmine, being up to 3.8% and 2.9%, respectively. Up to 3.2% of harmine was determined in the roots. The four ß-carboline derivatives, harmine, harmaline, harmane and harmalol were identified in the aerial parts. The highest inhibitory effect observed in seeds and the moderate effect of aerial parts could be explained by their harmine and harmaline content. In contrast, the very weak inhibition of the root extract, despite the presence of harmine, may tentatively be explained by the high concentration of harmol which can reduce Compound II of MPO to the native form. CONCLUSION: The inhibition of MPO by Peganum harmala ß-carboline alkaloids, herein reported for the first time, may explain the anti-inflammatory effect traditionally attributed to its herbal medicine.


Subject(s)
Alkaloids/pharmacology , Enzyme Inhibitors/pharmacology , Peganum/chemistry , Peroxidase/antagonists & inhibitors , Plant Extracts/chemistry , Alkaloids/isolation & purification , Binding Sites , Cholesterol, LDL/chemistry , Chromatography, High Pressure Liquid , Enzyme Inhibitors/isolation & purification , Ethnopharmacology , Humans , Inhibitory Concentration 50 , Molecular Docking Simulation , Molecular Structure , Oxidation-Reduction , Peroxidase/chemistry , Plant Components, Aerial/chemistry , Plant Roots/chemistry , Seeds/chemistry
6.
J Pharm Pharmacol ; 66(8): 1122-32, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24673477

ABSTRACT

OBJECTIVES: Major depressive disorder (MDD) is accompanied with an imbalance in the immune system and cardiovascular impairments, such as atherosclerosis. Several mechanisms have been pointed out to underlie this rather unexpected association, and among them the activity of myeloperoxidase (MPO). The aim of our study was to find compounds that inhibit both MPO and serotonin transporter (SERT) for treating MDD associated with cardiovascular diseases. METHODS: SERT inhibition was assessed with measuring of [(3) H]-serotonin uptake using HEK-293 MSR cells. MPO inhibition was determined by taurine chloramine test on 3-(aminoalkyl)-5-fluoroindole derivatives and on clinically relevant antidepressants. All kinetic measurements were performed using a temperature-controlled stopped-flow apparatus (model SX-18 MV). Promising lead compounds were docked onto SERT 3D structure modelled using the LeuT structure complexed to tryptophan (PDB code 3F3A). Their toxicological profile was also assessed. KEY FINDINGS: 3-(aminoalkyl)-5-fluoroindole derivative with 5 carbons on the side chain and paroxetine showed the best activity on both MPO and SERT at the nanomolar range. Paroxetine was found to be the first irreversible MPO inhibitor at nanomolar concentrations. CONCLUSIONS: Our results put forward the first hybrid molecule (compound 25) and drug (paroxetine) that can be especially used in MDD associated with inflammatory syndrome.


Subject(s)
Depressive Disorder, Major/drug therapy , Inflammation/drug therapy , Peroxidase/antagonists & inhibitors , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin Plasma Membrane Transport Proteins/pharmacology , Serotonin/metabolism , Antidepressive Agents/pharmacology , Cardiovascular Diseases/metabolism , Cell Line , Depressive Disorder, Major/metabolism , HEK293 Cells , Humans , Indoles/pharmacology , Inflammation/metabolism
7.
J Med Chem ; 56(10): 3943-58, 2013 May 23.
Article in English | MEDLINE | ID: mdl-23581551

ABSTRACT

Due to its production of potent antimicrobial oxidants including hypochlorous acid, human myeloperoxidase (MPO) plays a critical role in innate immunity and inflammatory diseases. Thus MPO is an attractive target in drug design. (Aminoalkyl)fluoroindole derivatives were detected to be very potent MPO inhibitors; however, they also promote inhibition of the serotonin reuptake transporter (SERT) at the same concentration range. Via structure-based drug design, a new series of MPO inhibitors derived from 3-alkylindole were synthesized and their effects were assessed on MPO-mediated taurine chlorination and low-density lipoprotein oxidation as well as on inhibition of SERT. The fluoroindole compound with three carbons in the side chain and one amide group exhibited a selectivity index of 35 (Ki/IC50) with high inhibition of MPO activity (IC50 = 18 nM), whereas its effect on SERT was in the micromolar range. Structure-function relationships, mechanism of action, and safety of the molecule are discussed.


Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Peroxidase/antagonists & inhibitors , Animals , Carboxylic Acids/chemistry , Crystallization , Drug Design , Enzyme Inhibitors/toxicity , Fluorine/chemistry , Humans , Indicators and Reagents , Indoles/chemistry , Lipoproteins, LDL/chemistry , Male , Models, Molecular , Nitrogen/chemistry , Oxidation-Reduction , Rats , Rats, Wistar , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity Relationship , Sulfur/chemistry , Taurine/analogs & derivatives , Taurine/pharmacology
8.
J Med Chem ; 55(16): 7208-18, 2012 Aug 23.
Article in English | MEDLINE | ID: mdl-22793255

ABSTRACT

Myeloperoxidase (MPO) is a major player of the innate immune defense system of human neutrophils and catalyzes the production of strong oxidizing and halogenating antimicrobial products. Because of its role in pathogenesis of many (inflammatory) diseases, there is great interest in the development of efficient and specific inhibitors. Here, using the X-ray structure of MPO, high-throughput molecular docking of 1350000 compounds was performed. From this virtual screening process, 81 were tested for inhibition of the chlorination activity of MPO, finally ending up with eight inhibiting candidates of different chemical structures. These were tested for inhibiting MPO-mediated low-density lipoprotein oxidation and for interacting with the relevant redox intermediates of MPO. The best inhibitors were bis-2,2'-[(dihydro-1,3(2H,4H)-pyrimidinediyl)bis(methylene)]phenol and 8-[(2-aminoethyl)amino]-3,7-dihydro-3-methyl-7-(3-phenoxypropyl)-1H-purine-2,6-dione. Both did not irreversibly inactivate the enzyme but efficiently trapped it in its compound II state. We discuss the mechanism of inactivation as well as pros and cons of the performed selection process.


Subject(s)
Databases, Chemical , Peroxidase/antagonists & inhibitors , Catalytic Domain , Drug Design , Halogenation , Humans , Kinetics , Lipoproteins, LDL/chemistry , Molecular Docking Simulation , Oxidation-Reduction , Purines/chemical synthesis , Purines/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship
SELECTION OF CITATIONS
SEARCH DETAIL
...