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1.
J Antimicrob Chemother ; 73(5): 1279-1290, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29420756

RESUMO

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.


Assuntos
Aminopiridinas/farmacologia , Antimaláricos/farmacologia , Fosfotransferases/antagonistas & inibidores , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Aminopiridinas/química , Aminopiridinas/isolamento & purificação , Antimaláricos/química , Antimaláricos/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Concentração Inibidora 50 , Testes de Sensibilidade Parasitária , Plasmodium falciparum/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/isolamento & purificação
2.
Macromol Rapid Commun ; 37(21): 1729-1734, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27616076

RESUMO

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.


Assuntos
Eletrólitos/química , Formazans/química , Hidrocarbonetos Aromáticos/química , Nanopartículas/química , Polímeros/química , Sais de Tetrazólio/química , Água/química , Oxirredução , Tamanho da Partícula , Propriedades de Superfície
3.
ACS Med Chem Lett ; 15(5): 626-630, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38746890

RESUMO

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.

4.
Phys Rev E ; 109(6-1): 064604, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-39020952

RESUMO

Through a one-dimensional colloidal model for epitaxial growth, we characterize the nucleation and aggregation processes occurring in a gap between adjacent islands. The timescales associated with deposition, diffusion, aggregation, and nucleation inside the gap are studied in terms of the parameters defining the interaction between colloidal particles. Numerical results from molecular-dynamics (MD) simulations are compared with analytical models and good agreement is found between both data sets. The results for the timescales are used to calculate the associated rates to generate kinetic Monte Carlo (KMC) simulations, which allow exploring larger systems and longer timescales in comparison with MD simulations. The KMC simulations reproduce the global behavior of the densities of islands and monomers as well as the gap length distribution between adjacent islands.

5.
J Phys Condens Matter ; 36(46)2024 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-39111342

RESUMO

The final structure and properties of layers grown by epitaxy techniques are determined in the very early stage of the process. This review describes one-dimensional models for epitaxial growth, emphasizing the basic theoretical concepts employed to analyze nucleation and aggregation phenomena in the submonolayer regime. The main findings regarding the evolution of quantities that define the properties of the system, such as monomer and island densities, and the associated island size, gap length, and capture zone distributions are discussed, as well as the analytical tools used to evaluate them. This review provides a concise overview of the most widely used algorithms for simulating growth processes, discusses relevant experimental results, and establishes connections with existing theoretical studies.

7.
Metabolites ; 12(2)2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35208165

RESUMO

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.

8.
J Med Chem ; 61(13): 5692-5703, 2018 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-29889526

RESUMO

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.


Assuntos
1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores , Malária/tratamento farmacológico , Naftiridinas/química , Naftiridinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , 1-Fosfatidilinositol 4-Quinase/química , Animais , Antimaláricos/química , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Modelos Animais de Doenças , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Camundongos , Modelos Moleculares , Naftiridinas/farmacocinética , Naftiridinas/uso terapêutico , Plasmodium falciparum/fisiologia , Conformação Proteica , Relação Estrutura-Atividade , Distribuição Tecidual
9.
J Med Chem ; 61(9): 4213-4227, 2018 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-29665687

RESUMO

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.


Assuntos
Descoberta de Drogas , Imidazóis/química , Imidazóis/farmacocinética , Malária/tratamento farmacológico , Plasmodium falciparum/fisiologia , Piridinas/química , Piridinas/farmacocinética , Animais , Modelos Animais de Doenças , Estabilidade de Medicamentos , Canal de Potássio ERG1/metabolismo , Humanos , Imidazóis/metabolismo , Imidazóis/uso terapêutico , Malária/genética , Malária/metabolismo , Camundongos , Piridinas/metabolismo , Piridinas/uso terapêutico , Solubilidade , Relação Estrutura-Atividade , Distribuição Tecidual , Água/química
10.
Chem Commun (Camb) ; (41): 4218-20, 2007 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-18217585

RESUMO

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.


Assuntos
Cobre/química , Compostos Organometálicos/síntese química , Rotaxanos/química , Catálise , Ligantes , Espectroscopia de Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/normas , Estrutura Molecular , Compostos Organometálicos/química , Oxirredução , Padrões de Referência , Estereoisomerismo
11.
J Med Chem ; 59(21): 9890-9905, 2016 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-27748596

RESUMO

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.


Assuntos
Antimaláricos/farmacologia , Estágios do Ciclo de Vida/efeitos dos fármacos , Malária/tratamento farmacológico , Doenças Parasitárias em Animais/tratamento farmacológico , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Pirazinas/farmacologia , Animais , Antimaláricos/química , Antimaláricos/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Células Hep G2 , Humanos , Camundongos , Camundongos SCID , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Doenças Parasitárias em Animais/parasitologia , Testes de Sensibilidade Parasitária , Plasmodium berghei/crescimento & desenvolvimento , Plasmodium falciparum/crescimento & desenvolvimento , Pirazinas/química , Pirazinas/metabolismo , Solubilidade , Relação Estrutura-Atividade , Água/química
12.
J Med Chem ; 58(18): 7572-9, 2015 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-26322748

RESUMO

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.


Assuntos
Antimaláricos/química , Pirimidinas/química , Administração Oral , Animais , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Cristalografia por Raios X , Resistência a Medicamentos , Canais de Potássio Éter-A-Go-Go/fisiologia , Feminino , Humanos , Malária/tratamento farmacológico , Malária/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Técnicas de Patch-Clamp , Plasmodium berghei , Plasmodium falciparum/efeitos dos fármacos , Conformação Proteica , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Solubilidade , Relação Estrutura-Atividade
13.
J Med Chem ; 58(21): 8713-22, 2015 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-26502160

RESUMO

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.


Assuntos
Antimaláricos/química , Antimaláricos/uso terapêutico , Malária/tratamento farmacológico , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Pirazóis/química , Pirazóis/uso terapêutico , Piridinas/química , Piridinas/uso terapêutico , Animais , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Fígado/parasitologia , Malária/parasitologia , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Camundongos , Pirazóis/farmacocinética , Pirazóis/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Relação Estrutura-Atividade
14.
J Med Chem ; 57(21): 8839-48, 2014 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-25313449

RESUMO

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.


Assuntos
Antimaláricos/síntese química , Piridazinas/síntese química , Sulfonas/síntese química , Animais , Antimaláricos/metabolismo , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Resistência a Múltiplos Medicamentos , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Humanos , Malária Falciparum/parasitologia , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Testes de Sensibilidade Parasitária , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Piridazinas/metabolismo , Piridazinas/farmacologia , Ratos Sprague-Dawley , Solubilidade , Relação Estrutura-Atividade , Sulfonas/metabolismo , Sulfonas/farmacologia
15.
J Med Chem ; 57(6): 2789-98, 2014 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-24568587

RESUMO

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.


Assuntos
Antimaláricos/síntese química , Antimaláricos/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Plasmodium/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/química , Piridazinas/síntese química , Piridazinas/farmacologia , Animais , Antimaláricos/farmacocinética , Disponibilidade Biológica , Desenho de Fármacos , Resistência a Medicamentos , Estabilidade de Medicamentos , Biblioteca Gênica , Meia-Vida , Ensaios de Triagem em Larga Escala , Malária/tratamento farmacológico , Malária/parasitologia , Malária Falciparum/tratamento farmacológico , Malária Falciparum/psicologia , Camundongos , Camundongos SCID , Testes de Sensibilidade Parasitária , Plasmodium berghei , Plasmodium falciparum/efeitos dos fármacos , Ratos , Relação Estrutura-Atividade
16.
J Med Chem ; 57(3): 1014-22, 2014 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-24446664

RESUMO

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.


Assuntos
Antimaláricos/síntese química , Pirimidinas/síntese química , Tiofenos/síntese química , Administração Oral , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Linhagem Celular , Bases de Dados de Compostos Químicos , Resistência a Múltiplos Medicamentos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Ensaios de Triagem em Larga Escala , Humanos , Malária/tratamento farmacológico , Malária/parasitologia , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Plasmodium berghei , Plasmodium falciparum/efeitos dos fármacos , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologia
17.
J Med Chem ; 56(21): 8860-71, 2013 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-24099149

RESUMO

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.


Assuntos
Aminopiridinas/farmacologia , Antimaláricos/farmacologia , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Administração Oral , Aminopiridinas/administração & dosagem , Aminopiridinas/química , Animais , Antimaláricos/administração & dosagem , Antimaláricos/química , Células CHO , Cricetulus , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Camundongos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Testes de Sensibilidade Parasitária , Ratos , Relação Estrutura-Atividade
18.
J Med Chem ; 55(24): 11022-30, 2012 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-23189922

RESUMO

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.


Assuntos
Aminopiridinas/síntese química , Antimaláricos/síntese química , Administração Oral , Aminopiridinas/química , Aminopiridinas/farmacologia , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Resistência a Múltiplos Medicamentos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Malária/tratamento farmacológico , Camundongos , Microssomos Hepáticos/metabolismo , Plasmodium berghei , Plasmodium falciparum/efeitos dos fármacos , Solubilidade , Relação Estrutura-Atividade
19.
J Med Chem ; 55(7): 3479-87, 2012 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-22390538

RESUMO

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).


Assuntos
Aminopiridinas/síntese química , Antimaláricos/síntese química , Administração Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Disponibilidade Biológica , Linhagem Celular , Cloroquina/farmacologia , Inibidores das Enzimas do Citocromo P-450 , Resistência a Medicamentos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Feminino , Humanos , Isoenzimas/antagonistas & inibidores , Malária/tratamento farmacológico , Camundongos , Microssomos Hepáticos/metabolismo , Plasmodium berghei , Plasmodium falciparum/efeitos dos fármacos , Coelhos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
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