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1.
ACS Med Chem Lett ; 15(5): 626-630, 2024 May 09.
Article de Anglais | MEDLINE | ID: mdl-38746890

RÉSUMÉ

To investigate the physicochemical properties of anti-schistosomal compounds reported between 2008 and 2023, a simple but extensive literature scrutiny was conducted. Keywords were searched in Chemical Abstracts Service (CAS) SciFinder and primary medicinal chemistry and pharmacology literature to locate publications with compounds displaying ex vivo and/or in vivo anti-schistosomal activity. A total of 57 repurposed U.S. Food and Drug Administration (FDA)-approved drugs, hits and their derivatives were manually extracted, curated and compared to known anti-schistosomal oral drugs in view of establishing trends of calculated critical molecular properties. From this analysis, it was determined that more than 65% of the compounds display cLogD7.4 > 3 values, whereas oxamniquine, metrifonate and praziquantel (PZQ), previous and currently used oral anti-schistosomal drugs, possess lower cLogD7.4 values (≤2.5). Furthermore, the lipophilicity associated with PZQ corresponds to a highly permeable and sparingly soluble compound, characteristics that favor drug absorption and compound penetration in the parasite. These physicochemical properties together with PZQ's anti-schistosomal activity make PZQ an essential medicine for the treatment of schistosomiasis and demonstrate the importance of finding the right balance among potency (e.g., EC50 < 5 and 0.5 µM), cell permeability (e.g., Papp > 2 × 106 cm/s) and kinetic aqueous solubility (e.g., >10 µM) to provide high-quality hits and/or leads for the discovery of new oral anti-schistosomal therapeutics.

2.
Metabolites ; 12(2)2022 Jan 18.
Article de Anglais | MEDLINE | ID: mdl-35208165

RÉSUMÉ

Ovidia pillopillo (Lloime) is an endemic species of the Valdivian Forest of Chile. Little is known on the chemistry and biological activity of this plant. In this study, the phenolic profile, antioxidant capacities and enzyme inhibition capacities (against tyrosinase and cholinesterase) of the plant were investigated for the first time. The phenolic profile of the plant was obtained by UHPLC-MS fingerprinting with high resolution, which showed the presence of several flavonoids and coumarins. The antioxidant potential was measured by FRAP and ORAC (45.56 ± 1.32; 25.33 ± 1.2 µmol Trolox equivalents/g dry plant, respectively) plus ABTS and DPPH methods (IC50 = 9.95 ± 0.05 and 6.65 ± 0.5 µg/mL, respectively). Moreover, the flavonoid and phenolic contents were determined (57.33 ± 0.82 and 38.42 ± 1.32, µg of Trolox and quercetin equivalents/100 g dry weight, respectively). The ethanolic extract showed cholinesterase (IC50 = 1.94 ± 0.07 and 2.73 ± 0.05 µg/mL, for AChE and BuChE, respectively) and tyrosinase (4.92 ± 0.05 µg/mL) enzyme inhibition activities. Based on these in vitro studies, in silico simulations were performed, which determined that the major compounds as ligands likely docked in the receptors of the enzymes. These results suggest that Ovidia pillopillo produce interesting special coumarins and flavonoids, which are potential candidates for the exploration and preparation of new medicines.

4.
J Med Chem ; 61(13): 5692-5703, 2018 07 12.
Article de Anglais | MEDLINE | ID: mdl-29889526

RÉSUMÉ

A novel 2,8-disubstituted-1,5-naphthyridine hit compound stemming from the open access Medicines for Malaria Venture Pathogen Box formed a basis for a hit-to-lead medicinal chemistry program. Structure-activity relationship investigations resulted in compounds with potent antiplasmodial activity against both chloroquine sensitive (NF54) and multidrug resistant (K1) strains of the human malaria parasite Plasmodium falciparum. In the humanized P. falciparum mouse efficacy model, one of the frontrunner compounds showed in vivo efficacy at an oral dose of 4 × 50 mg·kg-1. In vitro mode-of-action studies revealed Plasmodium falciparum phosphatidylinositol-4-kinase as the target.


Sujet(s)
1-Phosphatidylinositol 4-kinase/antagonistes et inhibiteurs , Paludisme/traitement médicamenteux , Naphtyridines/composition chimique , Naphtyridines/pharmacologie , Plasmodium falciparum/effets des médicaments et des substances chimiques , Plasmodium falciparum/enzymologie , 1-Phosphatidylinositol 4-kinase/composition chimique , Animaux , Antipaludiques/composition chimique , Antipaludiques/pharmacocinétique , Antipaludiques/pharmacologie , Antipaludiques/usage thérapeutique , Modèles animaux de maladie humaine , Conception de médicament , Antienzymes/composition chimique , Antienzymes/pharmacocinétique , Antienzymes/pharmacologie , Antienzymes/usage thérapeutique , Humains , Souris , Modèles moléculaires , Naphtyridines/pharmacocinétique , Naphtyridines/usage thérapeutique , Plasmodium falciparum/physiologie , Conformation des protéines , Relation structure-activité , Distribution tissulaire
5.
J Med Chem ; 61(9): 4213-4227, 2018 05 10.
Article de Anglais | MEDLINE | ID: mdl-29665687

RÉSUMÉ

Optimization of a chemical series originating from whole-cell phenotypic screening against the human malaria parasite, Plasmodium falciparum, led to the identification of two promising 2,6-disubstituted imidazopyridine compounds, 43 and 74. These compounds exhibited potent activity against asexual blood stage parasites that, together with their in vitro absorption, distribution, metabolism, and excretion (ADME) properties, translated to in vivo efficacy with clearance of parasites in the PfSCID mouse model for malaria within 48 h of treatment.


Sujet(s)
Découverte de médicament , Imidazoles/composition chimique , Imidazoles/pharmacocinétique , Paludisme/traitement médicamenteux , Plasmodium falciparum/physiologie , Pyridines/composition chimique , Pyridines/pharmacocinétique , Animaux , Modèles animaux de maladie humaine , Stabilité de médicament , Canal potassique ERG1/métabolisme , Humains , Imidazoles/métabolisme , Imidazoles/usage thérapeutique , Paludisme/génétique , Paludisme/métabolisme , Souris , Pyridines/métabolisme , Pyridines/usage thérapeutique , Solubilité , Relation structure-activité , Distribution tissulaire , Eau/composition chimique
6.
J Antimicrob Chemother ; 73(5): 1279-1290, 2018 05 01.
Article de Anglais | MEDLINE | ID: mdl-29420756

RÉSUMÉ

Objectives: Novel chemical tools to eliminate malaria should ideally target both the asexual parasites and transmissible gametocytes. Several imidazopyridazines (IMPs) and 2-aminopyridines (2-APs) have been described as potent antimalarial candidates targeting lipid kinases. However, these have not been extensively explored for stage-specific inhibition of gametocytes in Plasmodium falciparum parasites. Here we provide an in-depth evaluation of the gametocytocidal activity of compounds from these chemotypes and identify novel starting points for dual-acting antimalarials. Methods: We evaluated compounds against P. falciparum gametocytes using several assay platforms for cross-validation and stringently identified hits that were further profiled for stage specificity, speed of action and ex vivo efficacy. Physicochemical feature extraction and chemogenomic fingerprinting were applied to explore the kinase inhibition susceptibility profile. Results: We identified 34 compounds with submicromolar activity against late stage gametocytes, validated across several assay platforms. Of these, 12 were potent at <100 nM (8 were IMPs and 4 were 2-APs) and were also active against early stage gametocytes and asexual parasites, with >1000-fold selectivity towards the parasite over mammalian cells. Front-runner compounds targeted mature gametocytes within 48 h and blocked transmission to mosquitoes. The resultant chemogenomic fingerprint of parasites treated with the lead compounds revealed the importance of targeting kinases in asexual parasites and gametocytes. Conclusions: This study encompasses an in-depth evaluation of the kinase inhibitor space for gametocytocidal activity. Potent lead compounds have enticing dual activities and highlight the importance of targeting the kinase superfamily in malaria elimination strategies.


Sujet(s)
Aminopyridines/pharmacologie , Antipaludiques/pharmacologie , Phosphotransferases/antagonistes et inhibiteurs , Plasmodium falciparum/effets des médicaments et des substances chimiques , Plasmodium falciparum/enzymologie , Inhibiteurs de protéines kinases/pharmacologie , Aminopyridines/composition chimique , Aminopyridines/isolement et purification , Antipaludiques/composition chimique , Antipaludiques/isolement et purification , Survie cellulaire/effets des médicaments et des substances chimiques , Concentration inhibitrice 50 , Tests de sensibilité parasitaire , Plasmodium falciparum/composition chimique , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/isolement et purification
7.
J Med Chem ; 59(21): 9890-9905, 2016 11 10.
Article de Anglais | MEDLINE | ID: mdl-27748596

RÉSUMÉ

Introduction of water-solubilizing groups on the 5-phenyl ring of a 2-aminopyrazine series led to the identification of highly potent compounds against the blood life-cycle stage of the human malaria parasite Plasmodium falciparum. Several compounds displayed high in vivo efficacy in two different mouse models for malaria, P. berghei-infected mice and P. falciparum-infected NOD-scid IL-2Rγnull mice. One of the frontrunners, compound 3, was identified to also have good pharmacokinetics and additionally very potent activity against the liver and gametocyte parasite life-cycle stages.


Sujet(s)
Antipaludiques/pharmacologie , Étapes du cycle de vie/effets des médicaments et des substances chimiques , Paludisme/traitement médicamenteux , Parasitoses animales/traitement médicamenteux , Plasmodium berghei/effets des médicaments et des substances chimiques , Plasmodium falciparum/effets des médicaments et des substances chimiques , Pyrazines/pharmacologie , Animaux , Antipaludiques/composition chimique , Antipaludiques/métabolisme , Modèles animaux de maladie humaine , Relation dose-effet des médicaments , Canaux potassiques éther-à-go-go/antagonistes et inhibiteurs , Canaux potassiques éther-à-go-go/métabolisme , Cellules HepG2 , Humains , Souris , Souris SCID , Microsomes du foie/composition chimique , Microsomes du foie/métabolisme , Structure moléculaire , Parasitoses animales/parasitologie , Tests de sensibilité parasitaire , Plasmodium berghei/croissance et développement , Plasmodium falciparum/croissance et développement , Pyrazines/composition chimique , Pyrazines/métabolisme , Solubilité , Relation structure-activité , Eau/composition chimique
8.
Macromol Rapid Commun ; 37(21): 1729-1734, 2016 Nov.
Article de Anglais | MEDLINE | ID: mdl-27616076

RÉSUMÉ

The formation of redox-active, totally organic nanoparticles in water is achieved following a strategy similar to that used to form metal nanoparticles. It is based on two fundamental concepts: i) complexation through aromatic-aromatic interactions of a water-soluble precursor aromatic molecule with polyelectrolytes bearing complementary charged aromatic rings, and ii) reduction of the precursor molecule to achieve stabilized nanoparticles. Thus, formazan nanoparticles are synthesized by reduction of a tetrazolium salt with ascorbic acid using polyelectrolytes bearing benzene sulfonate residues of high linear aromatic density, but cannot be formed in the presence of nonaromatic polyelectrolytes. The red colored nanoparticles are efficiently encapsulated in calcium alginate beads, showing macroscopic homogeneity. Bleaching kinetics with chlorine show linear rates on the order of tenths of milli-meters per minute. A linear behavior of the dependence of the rate of bleaching on the chlorine concentration is found, showing the potential of the nanoparticles for chlorine sensing.


Sujet(s)
Électrolytes/composition chimique , Formazanes/composition chimique , Hydrocarbures aromatiques/composition chimique , Nanoparticules/composition chimique , Polymères/composition chimique , Sels de tétrazolium/composition chimique , Eau/composition chimique , Oxydoréduction , Taille de particule , Propriétés de surface
9.
J Med Chem ; 58(21): 8713-22, 2015 Nov 12.
Article de Anglais | MEDLINE | ID: mdl-26502160

RÉSUMÉ

Toward improving pharmacokinetics, in vivo efficacy, and selectivity over hERG, structure-activity relationship studies around the central core of antimalarial imidazopyridazines were conducted. This study led to the identification of potent pyrazolopyridines, which showed good in vivo efficacy and pharmacokinetics profiles. The lead compounds also proved to be very potent in the parasite liver and gametocyte stages, which makes them of high interest.


Sujet(s)
Antipaludiques/composition chimique , Antipaludiques/usage thérapeutique , Paludisme/traitement médicamenteux , Plasmodium berghei/effets des médicaments et des substances chimiques , Plasmodium falciparum/effets des médicaments et des substances chimiques , Pyrazoles/composition chimique , Pyrazoles/usage thérapeutique , Pyridines/composition chimique , Pyridines/usage thérapeutique , Animaux , Antipaludiques/pharmacocinétique , Antipaludiques/pharmacologie , Canaux potassiques éther-à-go-go/métabolisme , Humains , Foie/parasitologie , Paludisme/parasitologie , Paludisme à Plasmodium falciparum/traitement médicamenteux , Paludisme à Plasmodium falciparum/parasitologie , Souris , Pyrazoles/pharmacocinétique , Pyrazoles/pharmacologie , Pyridines/pharmacocinétique , Pyridines/pharmacologie , Rats , Relation structure-activité
10.
J Med Chem ; 58(18): 7572-9, 2015 Sep 24.
Article de Anglais | MEDLINE | ID: mdl-26322748

RÉSUMÉ

Based on the initial optimization of orally active antimalarial 2,4-diamino-thienopyrimidines and with the help of metabolite identification studies, a second generation of derivatives involving changes at the 2- and 4-positions of the thienopyrimidine core were synthesized. Improvements in the physiochemical properties resulted in the identification of 15a, 17a, 32, and 40 as lead molecules with improved in vivo exposure. Furthermore, analogue 40 exhibited excellent in vivo antimalarial activity when dosed orally at 50 mg/kg once daily for 4 days in the Plasmodium berghei mouse model, which is superior to the activity seen with previously reported compounds, and with a slightly improved hERG profile.


Sujet(s)
Antipaludiques/composition chimique , Pyrimidines/composition chimique , Administration par voie orale , Animaux , Antipaludiques/pharmacocinétique , Antipaludiques/pharmacologie , Cristallographie aux rayons X , Résistance aux substances , Canaux potassiques éther-à-go-go/physiologie , Femelle , Humains , Paludisme/traitement médicamenteux , Paludisme/parasitologie , Mâle , Souris , Souris de lignée BALB C , Microsomes du foie/métabolisme , Techniques de patch-clamp , Plasmodium berghei , Plasmodium falciparum/effets des médicaments et des substances chimiques , Conformation des protéines , Pyrimidines/pharmacocinétique , Pyrimidines/pharmacologie , Solubilité , Relation structure-activité
11.
J Med Chem ; 57(21): 8839-48, 2014 Nov 13.
Article de Anglais | MEDLINE | ID: mdl-25313449

RÉSUMÉ

On the basis of our recent results on a novel series of imidazopyridazine-based antimalarials, we focused on identifying compounds with improved aqueous solubility and hERG profile while maintaining metabolic stability and in vitro potency. Toward this objective, 41 compounds were synthesized and evaluated for antiplasmodial activity against NF54 (sensitive) and K1 (multidrug resistant) strains of the malaria parasite Plasmodium falciparum and evaluated for both aqueous solubility and metabolic stability. Selected compounds were tested for in vitro hERG activity and in vivo efficacy in the P. berghei mouse model. Several compounds were identified with significantly improved aqueous solubility, good metabolic stability, and a clean hERG profile relative to a previous frontrunner lead compound. A sulfoxide-based imidazopyridazine analog 45, arising from a prodrug-like strategy, was completely curative in the Plasmodium berghei mouse model at 4 × 50 mg/kg po.


Sujet(s)
Antipaludiques/synthèse chimique , Pyridazines/synthèse chimique , Sulfones/synthèse chimique , Animaux , Antipaludiques/métabolisme , Antipaludiques/pharmacocinétique , Antipaludiques/pharmacologie , Multirésistance aux médicaments , Canaux potassiques éther-à-go-go/effets des médicaments et des substances chimiques , Humains , Paludisme à Plasmodium falciparum/parasitologie , Mâle , Souris , Microsomes du foie/métabolisme , Tests de sensibilité parasitaire , Plasmodium berghei/effets des médicaments et des substances chimiques , Plasmodium falciparum/effets des médicaments et des substances chimiques , Pyridazines/métabolisme , Pyridazines/pharmacologie , Rat Sprague-Dawley , Solubilité , Relation structure-activité , Sulfones/métabolisme , Sulfones/pharmacologie
12.
J Med Chem ; 57(6): 2789-98, 2014 Mar 27.
Article de Anglais | MEDLINE | ID: mdl-24568587

RÉSUMÉ

A novel class of imidazopyridazines identified from whole cell screening of a SoftFocus kinase library was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant strain) and NF54 (sensitive strain). Structure-activity relationship studies led to the identification of highly potent compounds against both strains. Compound 35 was highly active (IC50: K1 = 6.3 nM, NF54 = 7.3 nM) and comparable in potency to artesunate, and 35 exhibited 98% activity in the in vivo P. berghei mouse model (4-day test by Peters) at 4 × 50 mg/kg po. Compound 35 was also assessed against P. falciparum in the in vivo SCID mouse model where the efficacy was found to be more consistent with the in vitro activity. Furthermore, 35 displayed high (78%) rat oral bioavailability with good oral exposure and plasma half-life. Mice exposure at the same dose was 10-fold lower than in rat, suggesting lower oral absorption and/or higher metabolic clearance in mice.


Sujet(s)
Antipaludiques/synthèse chimique , Antipaludiques/pharmacologie , Imidazoles/synthèse chimique , Imidazoles/pharmacologie , Plasmodium/effets des médicaments et des substances chimiques , Inhibiteurs de protéines kinases/synthèse chimique , Inhibiteurs de protéines kinases/pharmacologie , Protein kinases/composition chimique , Pyridazines/synthèse chimique , Pyridazines/pharmacologie , Animaux , Antipaludiques/pharmacocinétique , Biodisponibilité , Conception de médicament , Résistance aux substances , Stabilité de médicament , Banque de gènes , Période , Tests de criblage à haut débit , Paludisme/traitement médicamenteux , Paludisme/parasitologie , Paludisme à Plasmodium falciparum/traitement médicamenteux , Paludisme à Plasmodium falciparum/psychologie , Souris , Souris SCID , Tests de sensibilité parasitaire , Plasmodium berghei , Plasmodium falciparum/effets des médicaments et des substances chimiques , Rats , Relation structure-activité
13.
J Med Chem ; 57(3): 1014-22, 2014 Feb 13.
Article de Anglais | MEDLINE | ID: mdl-24446664

RÉSUMÉ

A novel series of 2,4-diaminothienopyrimidines with potential as antimalarials was identified from whole-cell high-throughput screening of a SoftFocus ion channel library. Synthesis and structure-activity relationship studies identified compounds with potent antiplasmodial activity and low in vitro cytotoxicity. Several of these analogues exhibited in vivo activity in the Plasmodium berghei mouse model when administered orally. However, inhibition of the hERG potassium channel was identified as a liability for this series.


Sujet(s)
Antipaludiques/synthèse chimique , Pyrimidines/synthèse chimique , Thiophènes/synthèse chimique , Administration par voie orale , Animaux , Antipaludiques/composition chimique , Antipaludiques/pharmacologie , Lignée cellulaire , Bases de données chimiques , Multirésistance aux médicaments , Canal potassique ERG1 , Canaux potassiques éther-à-go-go/antagonistes et inhibiteurs , Tests de criblage à haut débit , Humains , Paludisme/traitement médicamenteux , Paludisme/parasitologie , Mâle , Souris , Microsomes du foie/métabolisme , Plasmodium berghei , Plasmodium falciparum/effets des médicaments et des substances chimiques , Pyrimidines/composition chimique , Pyrimidines/pharmacologie , Rats , Rat Sprague-Dawley , Relation structure-activité , Thiophènes/composition chimique , Thiophènes/pharmacologie
14.
J Med Chem ; 56(21): 8860-71, 2013 Nov 14.
Article de Anglais | MEDLINE | ID: mdl-24099149

RÉSUMÉ

Replacement of the pyridine core of antimalarial 3,5-diaryl-2-aminopyridines led to the identification of a novel series of pyrazine analogues with potent oral antimalarial activity. However, other changes to the pyridine core and replacement or substitution of the 2-amino group led to loss of antimalarial activity. The 3,5-diaryl-2-aminopyrazine series showed impressive in vitro antiplasmodial activity against the K1 (multidrug resistant) and NF54 (sensitive) strains of Plasmodium falciparum in the nanomolar IC50 range of 6-94 nM while also demonstrating good in vitro metabolic stability in human liver microsomes. In the Plasmodium berghei mouse model, this series generally exhibited good efficacy at low oral doses. One of the frontrunner compounds, 4, displayed potent in vitro antiplasmodial activity with IC50 values of 8.4 and 10 nM against the K1 and NF54 strains, respectively. When evaluated in P. berghei -infected mice, compound 4 was completely curative at an oral dose of 4 × 10 mg/kg.


Sujet(s)
Aminopyridines/pharmacologie , Antipaludiques/pharmacologie , Plasmodium berghei/effets des médicaments et des substances chimiques , Plasmodium falciparum/effets des médicaments et des substances chimiques , Administration par voie orale , Aminopyridines/administration et posologie , Aminopyridines/composition chimique , Animaux , Antipaludiques/administration et posologie , Antipaludiques/composition chimique , Cellules CHO , Cricetulus , Modèles animaux de maladie humaine , Relation dose-effet des médicaments , Humains , Souris , Microsomes du foie/composition chimique , Microsomes du foie/métabolisme , Structure moléculaire , Tests de sensibilité parasitaire , Rats , Relation structure-activité
15.
J Med Chem ; 55(24): 11022-30, 2012 Dec 27.
Article de Anglais | MEDLINE | ID: mdl-23189922

RÉSUMÉ

In an effort to address potential cardiotoxicity liabilities identified with earlier frontrunner compounds, a number of new 3,5-diaryl-2-aminopyridine derivatives were synthesized. Several compounds exhibited potent antiplasmodial activity against both the multidrug resistant (K1) and sensitive (NF54) strains in the low nanomolar range. Some compounds displayed a significant reduction in potency in the hERG channel inhibition assay compared to previously reported frontrunner analogues. Several of these new analogues demonstrated promising in vivo efficacy in the Plasmodium berghei mouse model and will be further evaluated as potential clinical candidates. The SAR for in vitro antiplasmodial and hERG activity was delineated.


Sujet(s)
Aminopyridines/synthèse chimique , Antipaludiques/synthèse chimique , Administration par voie orale , Aminopyridines/composition chimique , Aminopyridines/pharmacologie , Animaux , Antipaludiques/composition chimique , Antipaludiques/pharmacologie , Multirésistance aux médicaments , Canal potassique ERG1 , Canaux potassiques éther-à-go-go/antagonistes et inhibiteurs , Humains , Paludisme/traitement médicamenteux , Souris , Microsomes du foie/métabolisme , Plasmodium berghei , Plasmodium falciparum/effets des médicaments et des substances chimiques , Solubilité , Relation structure-activité
16.
J Med Chem ; 55(7): 3479-87, 2012 Apr 12.
Article de Anglais | MEDLINE | ID: mdl-22390538

RÉSUMÉ

A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from phenotypic whole cell high-throughput screening of a commercially available SoftFocus kinase library. The compounds were evaluated in vitro for their antiplasmodial activity against K1 (chloroquine and drug-resistant strain) and NF54 (chloroquine-susceptible strain) as well as for their cytotoxicity. Synthesis and structure-activity studies identified a number of promising compounds with selective antiplasmodial activity. One of these frontrunner compounds, 15, was equipotent across the two strains (K1 = 25.0 nM, NF54 = 28.0 nM) and superior to chloroquine in the K1 strain (chloroquine IC(50) K1 = 194.0 nM). Compound 15 completely cured Plasmodium berghei-infected mice with a single oral dose of 30 mg/kg. Dose-response studies generated ED(50) and ED(90) values of 0.83 and 1.74 mg/kg for 15 in the standard four-dose Peters test. Pharmacokinetic studies in the rat indicated that this compound has good oral bioavailability (51% at 20 mg/kg) and a reasonable half-life (t(1/2) ∼ 7-8 h).


Sujet(s)
Aminopyridines/synthèse chimique , Antipaludiques/synthèse chimique , Administration par voie orale , Aminopyridines/pharmacocinétique , Aminopyridines/pharmacologie , Animaux , Antipaludiques/pharmacocinétique , Antipaludiques/pharmacologie , Biodisponibilité , Lignée cellulaire , Chloroquine/pharmacologie , Inhibiteurs des enzymes du cytochrome P-450 , Résistance aux substances , Canal potassique ERG1 , Canaux potassiques éther-à-go-go/antagonistes et inhibiteurs , Femelle , Humains , Isoenzymes/antagonistes et inhibiteurs , Paludisme/traitement médicamenteux , Souris , Microsomes du foie/métabolisme , Plasmodium berghei , Plasmodium falciparum/effets des médicaments et des substances chimiques , Lapins , Rats , Rat Sprague-Dawley , Relation structure-activité
17.
J Med Chem ; 54(21): 7713-9, 2011 Nov 10.
Article de Anglais | MEDLINE | ID: mdl-21966980

RÉSUMÉ

An aminomethylthiazole pyrazole carboxamide lead 3 with good in vitro antiplasmodial activity [IC(50): 0.08 µM (K1, chloroquine and multidrug resistant strain) and 0.07 µM (NF54, chloroquine sensitive strain)] and microsomal metabolic stability was identified from whole cell screening of a SoftFocus kinase library. Compound 3 also exhibited in vivo activity in the P. berghei mouse model at 4 × 50 mg/kg administration via the oral route, showing 99.5% activity and 9 days survival and showed low in vitro cytotoxicity. Pharmacokinetic studies in rats revealed good oral bioavailability (51% at 22 mg/kg) with a moderate rate of absorption, reasonable half-life (t(1/2) 3 h), and high volume of distribution with moderately high plasma and blood clearance after IV administration. Toward toxicity profiling, 3 exhibited moderate potential to inhibit CYP1A2 (IC(50) = 1.5 µM) and 2D6 (IC(50) = 0.4 µM) as well as having a potential hERG liability (IC(50) = 3.7 µM).


Sujet(s)
Antipaludiques/synthèse chimique , Thiazoles/synthèse chimique , Administration par voie orale , Animaux , Antipaludiques/pharmacocinétique , Antipaludiques/pharmacologie , Biodisponibilité , Inhibiteurs du cytochrome P-450 CYP1A2 , Interactions médicamenteuses , Résistance aux substances , Canaux potassiques éther-à-go-go/antagonistes et inhibiteurs , Humains , Techniques in vitro , Injections veineuses , Paludisme/traitement médicamenteux , Mâle , Souris , Microsomes/métabolisme , Tests de sensibilité parasitaire , Plasmodium berghei , Plasmodium falciparum/effets des médicaments et des substances chimiques , Rats , Rat Sprague-Dawley , Relation structure-activité , Thiazoles/pharmacocinétique , Thiazoles/pharmacologie
18.
Chem Commun (Camb) ; (41): 4218-20, 2007 Nov 07.
Article de Anglais | MEDLINE | ID: mdl-18217585

RÉSUMÉ

A series of mono- and bis-metallated [2]rotaxanes has been prepared using a CuAAC 'click' protocol that is compatible with metal-coordinated building blocks and ligands; the methodology provides a general means for appending a metal ion or complex to an organic scaffold via Cu(I)-catalysed 'click' chemistry, even when the molecule contains redox-active or kinetically labile metals or vacant ligand sites.


Sujet(s)
Cuivre/composition chimique , Composés organométalliques/synthèse chimique , Rotaxanes/composition chimique , Catalyse , Ligands , Spectroscopie par résonance magnétique/méthodes , Spectroscopie par résonance magnétique/normes , Structure moléculaire , Composés organométalliques/composition chimique , Oxydoréduction , Normes de référence , Stéréoisomérie
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