Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 21
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
2.
PLoS Pathog ; 14(9): e1007315, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30252911

RESUMO

Kinetoplastid parasites-trypanosomes and leishmanias-infect millions of humans and cause economically devastating diseases of livestock, and the few existing drugs have serious deficiencies. Benzoxaborole-based compounds are very promising potential novel anti-trypanosomal therapies, with candidates already in human and animal clinical trials. We investigated the mechanism of action of several benzoxaboroles, including AN7973, an early candidate for veterinary trypanosomosis. In all kinetoplastids, transcription is polycistronic. Individual mRNA 5'-ends are created by trans splicing of a short leader sequence, with coupled polyadenylation of the preceding mRNA. Treatment of Trypanosoma brucei with AN7973 inhibited trans splicing within 1h, as judged by loss of the Y-structure splicing intermediate, reduced levels of mRNA, and accumulation of peri-nuclear granules. Methylation of the spliced leader precursor RNA was not affected, but more prolonged AN7973 treatment caused an increase in S-adenosyl methionine and methylated lysine. Together, the results indicate that mRNA processing is a primary target of AN7973. Polyadenylation is required for kinetoplastid trans splicing, and the EC50 for AN7973 in T. brucei was increased three-fold by over-expression of the T. brucei cleavage and polyadenylation factor CPSF3, identifying CPSF3 as a potential molecular target. Molecular modeling results suggested that inhibition of CPSF3 by AN7973 is feasible. Our results thus chemically validate mRNA processing as a viable drug target in trypanosomes. Several other benzoxaboroles showed metabolomic and splicing effects that were similar to those of AN7973, identifying splicing inhibition as a common mode of action and suggesting that it might be linked to subsequent changes in methylated metabolites. Granule formation, splicing inhibition and resistance after CPSF3 expression did not, however, always correlate and prolonged selection of trypanosomes in AN7973 resulted in only 1.5-fold resistance. It is therefore possible that the modes of action of oxaboroles that target trypanosome mRNA processing might extend beyond CPSF3 inhibition.


Assuntos
Benzoxazóis/farmacologia , RNA de Protozoário/metabolismo , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei brucei/metabolismo , Animais , Benzoxazóis/química , Bovinos , Resistência a Medicamentos/genética , Cabras , Humanos , Camundongos , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Processamento Pós-Transcricional do RNA/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA de Protozoário/genética , Trans-Splicing/efeitos dos fármacos , Tripanossomicidas/química , Trypanosoma brucei brucei/genética , Trypanosoma congolense/efeitos dos fármacos , Trypanosoma congolense/genética , Trypanosoma congolense/metabolismo , Trypanosoma vivax/efeitos dos fármacos , Trypanosoma vivax/genética , Trypanosoma vivax/metabolismo , Tripanossomíase/tratamento farmacológico , Tripanossomíase/parasitologia
3.
Artigo em Inglês | MEDLINE | ID: mdl-29941635

RESUMO

The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistant Plasmodium falciparum and Plasmodium vivax clinical isolates. Excellent in vitro antiplasmodial activity translated into high efficacy in Plasmodium berghei and humanized P. falciparum NOD-scid IL-2Rγ null mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate in vivo intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next-generation Plasmodium PI4K inhibitor, UCT943, based on the combined preclinical data, has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent, and block the transmission of malaria.

4.
Bioorg Med Chem Lett ; 28(1): 6-10, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29169674

RESUMO

Novel l-valinate amide benzoxaboroles and analogues were designed and synthesized for a structure-activity-relationship (SAR) investigation to optimize the growth inhibitory activity against Trypanosoma congolense (T. congolense) and Trypanosoma vivax (T. vivax) parasites. The study identified 4-fluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-l-valinate (5, AN11736), which showed IC50 values of 0.15 nM against T. congolense and 1.3 nM against T. vivax, and demonstrated 100% efficacy with a single dose of 10 mg/kg against both T. congolense and T. vivax in mouse models of infection (IP dosing) and in the target animal, cattle, dosed intramuscularly. AN11736 has been advanced to early development studies.


Assuntos
Antiprotozoários/síntese química , Compostos de Boro/síntese química , Tripanossomíase Africana/tratamento farmacológico , Valina/análogos & derivados , Animais , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Compostos de Boro/farmacologia , Compostos de Boro/uso terapêutico , Bovinos , Camundongos , Relação Estrutura-Atividade , Trypanosoma congolense/efeitos dos fármacos , Trypanosoma vivax/efeitos dos fármacos , Tripanossomíase Africana/patologia , Tripanossomíase Africana/veterinária , Valina/síntese química , Valina/farmacologia , Valina/uso terapêutico
5.
Sci Transl Med ; 9(387)2017 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-28446690

RESUMO

As part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. Stemming from this series, we found that the derivative, MMV390048, lacked cross-resistance with current drugs used to treat malaria. This compound was efficacious against all Plasmodium life cycle stages, apart from late hypnozoites in the liver. Efficacy was shown in the humanized Plasmodium falciparum mouse model, and modest reductions in mouse-to-mouse transmission were achieved in the Plasmodium berghei mouse model. Experiments in monkeys revealed the ability of MMV390048 to be used for full chemoprotection. Although MMV390048 was not able to eliminate liver hypnozoites, it delayed relapse in a Plasmodium cynomolgi monkey model. Both genomic and chemoproteomic studies identified a kinase of the Plasmodium parasite, phosphatidylinositol 4-kinase, as the molecular target of MMV390048. The ability of MMV390048 to block all life cycle stages of the malaria parasite suggests that this compound should be further developed and may contribute to malaria control and eradication as part of a single-dose combination treatment.


Assuntos
1-Fosfatidilinositol 4-Quinase/antagonistas & inibidores , Aminopiridinas/uso terapêutico , Antimaláricos/uso terapêutico , Sulfonas/uso terapêutico , Aminopiridinas/farmacologia , Animais , Antimaláricos/farmacologia , Feminino , Malária/tratamento farmacológico , Malária/enzimologia , Masculino , Camundongos , Camundongos SCID , Testes de Sensibilidade Parasitária , Plasmodium/efeitos dos fármacos , Plasmodium/patogenicidade , Sulfonas/farmacologia
6.
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
7.
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
8.
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
9.
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
10.
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
11.
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
12.
Malar J ; 12: 424, 2013 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-24237770

RESUMO

BACKGROUND: Recent whole cell in vitro screening campaigns identified thousands of compounds that are active against asexual blood stages of Plasmodium falciparum at submicromolar concentrations. These hits have been made available to the public, providing many novel chemical starting points for anti-malarial drug discovery programmes. Knowing which of these hits are fast-acting compounds is of great interest. Firstly, a fast action will ensure rapid relief of symptoms for the patient. Secondly, by rapidly reducing the parasitaemia, this could minimize the occurrence of mutations leading to new drug resistance mechanisms.An in vitro assay that provides information about the speed of action of test compounds has been developed by researchers at GlaxoSmithKline (GSK) in Spain. This assay also provides an in vitro measure for the ratio between parasitaemia at the onset of drug treatment and after one intra-erythrocytic cycle (parasite reduction ratio, PRR). Both parameters are needed to determine in vitro killing rates of anti-malarial compounds. A drawback of the killing rate assay is that it takes a month to obtain first results. METHODS: The approach described in the present study is focused only on the speed of action of anti-malarials. This has the advantage that initial results can be achieved within 4-7 working days, which helps to distinguish between fast and slow-acting compounds relatively quickly. It is expected that this new assay can be used as a filter in the early drug discovery phase, which will reduce the number of compounds progressing to secondary, more time-consuming assays like the killing rate assay. RESULTS: The speed of action of a selection of seven anti-malarial compounds was measured with two independent experimental procedures using modifications of the standard [3H]hypoxanthine incorporation assay. Depending on the outcome of both assays, the tested compounds were classified as either fast or non-fast-acting. CONCLUSION: The results obtained for the anti-malarials chloroquine, artesunate, atovaquone, and pyrimethamine are consistent with previous observations, suggesting the methodology is a valid way to rapidly identify fast-acting anti-malarial compounds. Another advantage of the approach is its ability to discriminate between static or cidal compound effects.


Assuntos
Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Concentração Inibidora 50 , Testes de Sensibilidade Parasitária/métodos , Fatores de Tempo
13.
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
14.
J Med Chem ; 56(20): 7750-4, 2013 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-23927599

RESUMO

In the second part of this Miniperspectives series, we highlight our medicinal chemistry efforts involving progression of hits from whole cell high-throughput screening (HTS) of a SoftFocus kinase library against the malaria parasite Plasmodium falciparum . Successful SAR exploration in Hit-to-Lead and Lead Optimization efforts leading to the selection of a preclinical development candidate are demonstrated. Related efforts by researchers from Broad/Genzyme, Anacor, and GSK are briefly covered.


Assuntos
Antimaláricos/uso terapêutico , Química Farmacêutica/métodos , Descoberta de Drogas/métodos , Administração Oral , Antimaláricos/administração & dosagem , Antimaláricos/química , Avaliação Pré-Clínica de Medicamentos , Humanos , Malária Falciparum/parasitologia , Malária Falciparum/prevenção & controle , Estrutura Molecular , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-Atividade
15.
Future Med Chem ; 4(18): 2265-77, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23234550

RESUMO

The current state of antimalarial drug resistance emphasizes the need for new therapies with novel modes of action that will add a significant benefit compared with current standards. In this regard, high throughput phenotypic whole-cell screening aids the discovery of novel antiplasmodial scaffolds that are inherently suited to hit-to-lead and lead-optimization efforts. The aminothiazoles and aminopyridines exemplify two such compound classes stemming from whole-cell screening. Respective structure-activity relationship determinations and subsequent optimization around these scaffolds led to frontrunner compounds in each series, which possess the desired antimalarial efficacy, bioavailability and metabolic stability to further progress medicinal chemistry programs.


Assuntos
Aminopiridinas/química , Aminopiridinas/farmacologia , Antimaláricos/química , Antimaláricos/farmacologia , Malária Falciparum/tratamento farmacológico , Tiazóis/química , Tiazóis/farmacologia , Animais , Bases de Dados de Produtos Farmacêuticos , Resistência a Medicamentos , Humanos , Malária Falciparum/parasitologia , Testes de Sensibilidade Parasitária/métodos , Plasmodium falciparum/citologia , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-Atividade
16.
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
17.
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
18.
J Med Chem ; 54(21): 7713-9, 2011 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-21966980

RESUMO

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).


Assuntos
Antimaláricos/síntese química , Tiazóis/síntese química , Administração Oral , Animais , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Disponibilidade Biológica , Inibidores do Citocromo P-450 CYP1A2 , Interações Medicamentosas , Resistência a Medicamentos , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Técnicas In Vitro , Injeções Intravenosas , Malária/tratamento farmacológico , Masculino , Camundongos , Microssomos/metabolismo , Testes de Sensibilidade Parasitária , Plasmodium berghei , Plasmodium falciparum/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia
19.
Bioorg Med Chem Lett ; 19(2): 401-5, 2009 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-19091562

RESUMO

A series of 2-pyridyl pyrimidines, reported inhibitors of Plasmodium falciparum methionine aminopeptidase 1b were synthesized and evaluated for their antiplasmodial activities. An analysis of physicochemical properties demonstrated a link between lipophilicity and antiparasitic activity. Cross screening of the library against cultured Leishmania donovani parasites revealed this class of compounds as potent inhibitors of parasite development in vitro.


Assuntos
Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Leishmania donovani/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Pirimidinas/síntese química , Pirimidinas/farmacologia , Animais , Avaliação Pré-Clínica de Medicamentos , Relação Estrutura-Atividade
20.
Bioorg Med Chem Lett ; 19(2): 481-4, 2009 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-19054674

RESUMO

A dual activity, conjugated approach has been taken to form hybrid molecules of two known antimalarial drugs, chloroquine (CQ) and the non-sedating H1 antagonist astemizole. A variety of linkers were investigated to conjugate the two agents into one molecule. Compounds 5-8 possessed improved in vitro activity against a CQ-resistant strain of Plasmodium falciparum, and examples 7 and 8 were active in vivo in mouse models of malaria.


Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Astemizol/química , Cloroquina/química , Plasmodium falciparum/efeitos dos fármacos , Animais , Antimaláricos/uso terapêutico , Astemizol/farmacologia , Astemizol/uso terapêutico , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Malária Falciparum/tratamento farmacológico , Camundongos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA