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1.
J Med Chem ; 62(6): 3135-3146, 2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30830766

RESUMO

Cryptosporidium is a leading cause of pediatric diarrhea worldwide. Currently, there is neither a vaccine nor a consistently effective drug available for this disease. Selective 5-aminopyrazole-4-carboxamide-based bumped-kinase inhibitors (BKIs) are effective in both in vitro and in vivo models of Cryptosporidium parvum. Potential cardiotoxicity in some BKIs led to the continued exploration of the 5-aminopyrazole-4-carboxamide scaffold to find safe and effective drug candidates for Cryptosporidium. A series of newly designed BKIs were tested for efficacy against C. parvum using in vitro and in vivo (mouse infection model) assays and safety issues. Compound 6 (BKI 1708) was found to be efficacious at 8 mg/kg dosed once daily (QD) for 5 days with no observable signs of toxicity up to 200 mg/kg dosed QD for 7 days. Compound 15 (BKI 1770) was found to be efficacious at 30 mg/kg dosed twice daily (BID) for 5 days with no observable signs of toxicity up to 300 mg/kg dosed QD for 7 days. Compounds 6 and 15 are promising preclinical leads for cryptosporidiosis therapy with acceptable safety parameters and efficacy in the mouse model of cryptosporidiosis.


Assuntos
Antiprotozoários/uso terapêutico , Ácidos Carboxílicos/química , Criptosporidiose/tratamento farmacológico , Pirazóis/farmacologia , Animais , Antiprotozoários/farmacocinética , Linhagem Celular , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Desenvolvimento de Medicamentos , Humanos , Interferon gama/genética , Camundongos , Camundongos Knockout , Pirazóis/química , Pirazóis/farmacocinética
2.
J Infect Dis ; 219(9): 1464-1473, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30423128

RESUMO

Bumped kinase inhibitors (BKIs) have been shown to be potent inhibitors of Toxoplasma gondii calcium-dependent protein kinase 1. Pyrazolopyrimidine and 5-aminopyrazole-4-carboxamide scaffold-based BKIs are effective in acute and chronic experimental models of toxoplasmosis. Through further exploration of these 2 scaffolds and a new pyrrolopyrimidine scaffold, additional compounds have been identified that are extremely effective against acute experimental toxoplasmosis. The in vivo efficacy of these BKIs demonstrates that the cyclopropyloxynaphthyl, cyclopropyloxyquinoline, and 2-ethoxyquinolin-6-yl substituents are associated with efficacy across scaffolds. In addition, a broad range of plasma concentrations after oral dosing resulted from small structural changes to the BKIs. These select BKIs include anti-Toxoplasma compounds that are effective against acute experimental toxoplasmosis and are not toxic in human cell assays, nor to mice when administered for therapy. The BKIs described here are promising late leads for improving anti-Toxoplasma therapy.


Assuntos
Inibidores de Proteínas Quinases/uso terapêutico , Proteínas de Protozoários/antagonistas & inibidores , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Toxoplasmose Animal/tratamento farmacológico , Toxoplasmose Cerebral/tratamento farmacológico , Administração Oral , Animais , Área Sob a Curva , Feminino , Técnicas In Vitro , Camundongos , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/sangue , Pirazóis/farmacologia , Pirimidinas/sangue , Pirimidinas/farmacologia
3.
Int J Parasitol Drugs Drug Resist ; 8(1): 112-124, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29501973

RESUMO

Neospora caninum is one of the main causes of abortion in cattle, and recent studies have highlighted its relevance as an abortifacient in small ruminants. Vaccines or drugs for the control of neosporosis are lacking. Bumped kinase inhibitors (BKIs), which are ATP-competitive inhibitors of calcium dependent protein kinase 1 (CDPK1), were shown to be highly efficacious against several apicomplexan parasites in vitro and in laboratory animal models. We here present the pharmacokinetics, safety and efficacy of BKI-1553 in pregnant ewes and foetuses using a pregnant sheep model of N. caninum infection. BKI-1553 showed exposure in pregnant ewes with trough concentrations of approximately 4 µM, and of 1  µM in foetuses. Subcutaneous BKI-1553 administration increased rectal temperatures shortly after treatment, and resulted in dermal nodules triggering a slight monocytosis after repeated doses at short intervals. BKI-1553 treatment decreased fever in infected pregnant ewes already after two applications, resulted in a 37-50% reduction in foetal mortality, and modulated immune responses; IFNγ levels were increased early after infection and IgG levels were reduced subsequently. N. caninum was abundantly found in placental tissues; however, parasite detection in foetal brain tissue decreased from 94% in the infected/untreated group to 69-71% in the treated groups. In summary, BKI-1553 confers partial protection against abortion in a ruminant experimental model of N. caninum infection during pregnancy. In addition, reduced parasite detection, parasite load and lesions in foetal brains were observed.


Assuntos
Coccidiose/tratamento farmacológico , Estágios do Ciclo de Vida/efeitos dos fármacos , Neospora/efeitos dos fármacos , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Aborto Animal/prevenção & controle , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/parasitologia , Coccidiose/imunologia , Coccidiose/parasitologia , Feminino , Feto/efeitos dos fármacos , Febre/induzido quimicamente , Imunoglobulina G/sangue , Interferon gama/sangue , Neospora/imunologia , Neospora/isolamento & purificação , Carga Parasitária , Gravidez , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Ovinos
4.
Int J Parasitol ; 47(12): 753-763, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28899690

RESUMO

Improvements have been made to the safety and efficacy of bumped kinase inhibitors, and they are advancing toward human and animal use for treatment of cryptosporidiosis. As the understanding of bumped kinase inhibitor pharmacodynamics for cryptosporidiosis therapy has increased, it has become clear that better compounds for efficacy do not necessarily require substantial systemic exposure. We now have a bumped kinase inhibitor with reduced systemic exposure, acceptable safety parameters, and efficacy in both the mouse and newborn calf models of cryptosporidiosis. Potential cardiotoxicity is the limiting safety parameter to monitor for this bumped kinase inhibitor. This compound is a promising pre-clinical lead for cryptosporidiosis therapy in animals and humans.


Assuntos
Criptosporidiose/tratamento farmacológico , Cryptosporidium parvum/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Administração Oral , Animais , Animais Recém-Nascidos , Bovinos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Coração/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Interferon gama/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Testes de Mutagenicidade , Gravidez , Ligação Proteica , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/toxicidade , Segurança
5.
J Infect Dis ; 215(8): 1275-1284, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28329187

RESUMO

Bumped kinase inhibitors (BKIs) of Cryptosporidium parvum calcium-dependent protein kinase 1 (CpCDPK1) are leading candidates for treatment of cryptosporidiosis-associated diarrhea. Potential cardiotoxicity related to anti-human ether-à-go-go potassium channel (hERG) activity of the first-generation anti-Cryptosporidium BKIs triggered further testing for efficacy. A luminescence assay adapted for high-throughput screening was used to measure inhibitory activities of BKIs against C. parvum in vitro. Furthermore, neonatal and interferon γ knockout mouse models of C. parvum infection identified BKIs with in vivo activity. Additional iterative experiments for optimum dosing and selecting BKIs with minimum levels of hERG activity and frequencies of other safety liabilities included those that investigated mammalian cell cytotoxicity, C. parvum proliferation inhibition in vitro, anti-human Src inhibition, hERG activity, in vivo pharmacokinetic data, and efficacy in other mouse models. Findings of this study suggest that fecal concentrations greater than parasite inhibitory concentrations correlate best with effective therapy in the mouse model of cryptosporidiosis, but a more refined model for efficacy is needed.


Assuntos
Antiprotozoários/administração & dosagem , Criptosporidiose/tratamento farmacológico , Cryptosporidium parvum/efeitos dos fármacos , Inibidores de Proteínas Quinases/administração & dosagem , Administração Oral , Animais , Diarreia/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Knockout , Camundongos SCID
6.
ACS Infect Dis ; 3(1): 34-44, 2017 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-27798837

RESUMO

Plasmodium falciparum (Pf) prolyl-tRNA synthetase (ProRS) is one of the few chemical-genetically validated drug targets for malaria, yet highly selective inhibitors have not been described. In this paper, approximately 40,000 compounds were screened to identify compounds that selectively inhibit PfProRS enzyme activity versus Homo sapiens (Hs) ProRS. X-ray crystallography structures were solved for apo, as well as substrate- and inhibitor-bound forms of PfProRS. We identified two new inhibitors of PfProRS that bind outside the active site. These two allosteric inhibitors showed >100 times specificity for PfProRS compared to HsProRS, demonstrating this class of compounds could overcome the toxicity related to HsProRS inhibition by halofuginone and its analogues. Initial medicinal chemistry was performed on one of the two compounds, guided by the cocrystallography of the compound with PfProRS, and the results can instruct future medicinal chemistry work to optimize these promising new leads for drug development against malaria.


Assuntos
Aminoacil-tRNA Sintetases/antagonistas & inibidores , Antimaláricos/farmacologia , Inibidores Enzimáticos/farmacologia , Plasmodium falciparum/enzimologia , Sítios de Ligação , Clonagem Molecular , Descoberta de Drogas , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Modelos Moleculares , Plasmodium falciparum/efeitos dos fármacos , Conformação Proteica , Bibliotecas de Moléculas Pequenas
7.
J Infect Dis ; 214(12): 1856-1864, 2016 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-27923949

RESUMO

Cryptosporidiosis, caused by the apicomplexan parasite Cryptosporidium parvum, is a diarrheal disease that has produced a large global burden in mortality and morbidity in humans and livestock. There are currently no consistently effective parasite-specific pharmaceuticals available for this disease. Bumped kinase inhibitors (BKIs) specific for parasite calcium-dependent protein kinases (CDPKs) have been shown to reduce infection in several parasites having medical and veterinary importance, including Toxoplasma gondii, Plasmodium falciparum, and C. parvum In the present study, BKIs were screened for efficacy against C. parvum infection in the neonatal mouse model. Three BKIs were then selected for safety and clinical efficacy evaluation in the calf model for cryptosporidiosis. Significant BKI treatment effects were observed for virtually all clinical and parasitological scoring parameters, including diarrhea severity, oocyst shedding, and overall health. These results provide proof of concept for BKIs as therapeutic drug leads in an animal model for human cryptosporidiosis.


Assuntos
Antiprotozoários/administração & dosagem , Doenças dos Bovinos/tratamento farmacológico , Criptosporidiose/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Animais , Animais Recém-Nascidos , Antiprotozoários/efeitos adversos , Bovinos , Cryptosporidium parvum/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Camundongos Endogâmicos BALB C , Inibidores de Proteínas Quinases/efeitos adversos , Resultado do Tratamento
8.
Int J Parasitol ; 46(13-14): 871-880, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27729271

RESUMO

Sarcocystis neurona is the most frequent cause of equine protozoal myeloencephalitis, a debilitating neurological disease of horses that can be difficult to treat. We identified SnCDPK1, the S. neurona homologue of calcium-dependent protein kinase 1 (CDPK1), a validated drug target in Toxoplasma gondii. SnCDPK1 shares the glycine "gatekeeper" residue of the well-characterized T. gondii enzyme, which allows the latter to be targeted by bumped kinase inhibitors. This study presents detailed molecular and phenotypic evidence that SnCDPK1 can be targeted for rational drug development. Recombinant SnCDPK1 was tested against four bumped kinase inhibitors shown to potently inhibit both T. gondii (Tg) CDPK1 and T. gondii tachyzoite growth. SnCDPK1 was inhibited by low nanomolar concentrations of these BKIs and S. neurona growth was inhibited at 40-120nM concentrations. Thermal shift assays confirmed these bumped kinase inhibitors bind CDPK1 in S. neurona cell lysates. Treatment with bumped kinase inhibitors before or after invasion suggests that bumped kinase inhibitors interfere with S. neurona mammalian host cell invasion in the 0.5-2.5µM range but interfere with intracellular division at 2.5µM. In vivo proof-of-concept experiments were performed in a murine model of S. neurona infection. The experimental infected groups treated for 30days with compound BKI-1553 (n=10 mice) had no signs of disease, while the infected control group had severe signs and symptoms of infection. Elevated antibody responses were found in 100% of control infected animals, but only 20% of BKI-1553 treated infected animals. Parasites were found in brain tissues of 100% of the control infected animals, but only in 10% of the BKI-1553 treated animals. The bumped kinase inhibitors used in these assays have been chemically optimized for potency, selectivity and pharmacokinetic properties, and hence are good candidates for treatment of equine protozoal myeloencephalitis.


Assuntos
Encefalomielite/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/efeitos dos fármacos , Sarcocystis/enzimologia , Sarcocistose/tratamento farmacológico , Animais , Linhagem Celular , Chlorocebus aethiops , Encefalomielite/parasitologia , Feminino , Doenças dos Cavalos/tratamento farmacológico , Doenças dos Cavalos/parasitologia , Cavalos , Interferon gama/genética , Masculino , Camundongos , Camundongos Knockout , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Coelhos , Sarcocystis/efeitos dos fármacos , Temperatura , Toxoplasma/efeitos dos fármacos , Toxoplasma/enzimologia
9.
J Med Chem ; 59(13): 6531-46, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27309760

RESUMO

New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by the protozoan parasite Toxoplasma gondii. To this end, we previously developed a potent and selective inhibitor (compound 1) of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activity in vitro and in vivo. Unfortunately, 1 has potent human ether-a-go-go-related gene (hERG) inhibitory activity, associated with long Q-T syndrome, and consequently presents a cardiotoxicity risk. Here, we describe the identification of an optimized TgCDPK1 inhibitor 32, which does not have a hERG liability and possesses a favorable pharmacokinetic profile in small and large animals. 32 is CNS-penetrant and highly effective in acute and latent mouse models of T. gondii infection, significantly reducing the amount of parasite in the brain, spleen, and peritoneal fluid and reducing brain cysts by >85%. These properties make 32 a promising lead for the development of a new antitoxoplasmosis therapy.


Assuntos
Antiprotozoários/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Desenho de Fármacos , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Toxoplasma/efeitos dos fármacos , Toxoplasmose/tratamento farmacológico , Administração Oral , Animais , Antiprotozoários/administração & dosagem , Antiprotozoários/química , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/metabolismo , Feminino , Haplorrinos , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Testes de Sensibilidade Parasitária , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Toxoplasma/enzimologia , Toxoplasmose/metabolismo
10.
PLoS One ; 11(3): e0149996, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26934697

RESUMO

In 2010 the identities of thousands of anti-Plasmodium compounds were released publicly to facilitate malaria drug development. Understanding these compounds' mechanisms of action--i.e., the specific molecular targets by which they kill the parasite--would further facilitate the drug development process. Given that kinases are promising anti-malaria targets, we screened ~14,000 cell-active compounds for activity against five different protein kinases. Collections of cell-active compounds from GlaxoSmithKline (the ~13,000-compound Tres Cantos Antimalarial Set, or TCAMS), St. Jude Children's Research Hospital (260 compounds), and the Medicines for Malaria Venture (the 400-compound Malaria Box) were screened in biochemical assays of Plasmodium falciparum calcium-dependent protein kinases 1 and 4 (CDPK1 and CDPK4), mitogen-associated protein kinase 2 (MAPK2/MAP2), protein kinase 6 (PK6), and protein kinase 7 (PK7). Novel potent inhibitors (IC50 < 1 µM) were discovered for three of the kinases: CDPK1, CDPK4, and PK6. The PK6 inhibitors are the most potent yet discovered for this enzyme and deserve further scrutiny. Additionally, kinome-wide competition assays revealed a compound that inhibits CDPK4 with few effects on ~150 human kinases, and several related compounds that inhibit CDPK1 and CDPK4 yet have limited cytotoxicity to human (HepG2) cells. Our data suggest that inhibiting multiple Plasmodium kinase targets without harming human cells is challenging but feasible.


Assuntos
Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/metabolismo , Proteínas Quinases/metabolismo , Cálcio/metabolismo , Linhagem Celular Tumoral , Células Hep G2 , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Protozoários/metabolismo
11.
J Infect Dis ; 209(2): 275-84, 2014 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-24123773

RESUMO

Malaria parasites are transmitted by mosquitoes, and blocking parasite transmission is critical in reducing or eliminating malaria in endemic regions. Here, we report the pharmacological characterization of a new class of malaria transmission-blocking compounds that acts via the inhibition of Plasmodia CDPK4 enzyme. We demonstrate that these compounds achieved selectivity over mammalian kinases by capitalizing on a small serine gatekeeper residue in the active site of the Plasmodium CDPK4 enzyme. To directly confirm the mechanism of action of these compounds, we generated P. falciparum parasites that express a drug-resistant methionine gatekeeper (S147 M) CDPK4 mutant. Mutant parasites showed a shift in exflagellation EC50 relative to the wild-type strains in the presence of compound 1294, providing chemical-genetic evidence that CDPK4 is the target of the compound. Pharmacokinetic analyses suggest that coformulation of this transmission-blocking agent with asexual stage antimalarials such as artemisinin combination therapy (ACT) is a promising option for drug delivery that may reduce transmission of malaria including drug-resistant strains. Ongoing studies include refining the compounds to improve efficacy and toxicological properties for efficient blocking of malaria transmission.


Assuntos
Antimaláricos/metabolismo , Inibidores Enzimáticos/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Proteínas Quinases/metabolismo , Proteínas de Protozoários/antagonistas & inibidores , Animais , Antimaláricos/isolamento & purificação , Antimaláricos/farmacocinética , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacocinética , Flagelos/efeitos dos fármacos , Flagelos/fisiologia , Camundongos , Plasmodium falciparum/fisiologia
12.
Trends Pharmacol Sci ; 29(2): 62-71, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18190973

RESUMO

An established paradigm in current drug development is (i) to identify a single protein target whose inhibition is likely to result in the successful treatment of a disease of interest; (ii) to assay experimentally large libraries of small-molecule compounds in vitro and in vivo to identify promising inhibitors in model systems; and (iii) to determine whether the findings are extensible to humans. This complex process, which is largely based on trial and error, is risk-, time- and cost-intensive. Computational (virtual) screening of drug-like compounds simultaneously against the atomic structures of multiple protein targets, taking into account protein-inhibitor dynamics, might help to identify lead inhibitors more efficiently, particularly for complex drug-resistant diseases. Here we discuss the potential benefits of this approach, using HIV-1 and Plasmodium falciparum infections as examples. We propose a virtual drug discovery 'pipeline' that will not only identify lead inhibitors efficiently, but also help minimize side-effects and toxicity, thereby increasing the likelihood of successful therapies.


Assuntos
Biologia Computacional/métodos , Sistemas de Liberação de Medicamentos/métodos , Desenho de Fármacos , Animais , Fármacos Anti-HIV/farmacologia , Antimaláricos/farmacologia , Simulação por Computador , HIV-1/efeitos dos fármacos , Humanos , Plasmodium falciparum/efeitos dos fármacos
13.
Antimicrob Agents Chemother ; 51(10): 3659-71, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17606674

RESUMO

New antimalarials are urgently needed. We have shown that tetrahydroquinoline (THQ) protein farnesyltransferase (PFT) inhibitors (PFTIs) are effective against the Plasmodium falciparum PFT and are effective at killing P. falciparum in vitro. Previously described THQ PFTIs had limitations of poor oral bioavailability and rapid clearance from the circulation of rodents. In this paper, we validate both the Caco-2 cell permeability model for predicting THQ intestinal absorption and the in vitro liver microsome model for predicting THQ clearance in vivo. Incremental improvements in efficacy, oral absorption, and clearance rate were monitored by in vitro tests; and these tests were followed up with in vivo absorption, distribution, metabolism, and excretion studies. One compound, PB-93, achieved cure when it was given orally to P. berghei-infected rats every 8 h for a total of 72 h. However, PB-93 was rapidly cleared, and dosing every 12 h failed to cure the rats. Thus, the in vivo results corroborate the in vitro pharmacodynamics and demonstrate that 72 h of continuous high-level exposure to PFTIs is necessary to kill plasmodia. The metabolism of PB-93 was demonstrated by a novel technique that relied on double labeling with a radiolabel and heavy isotopes combined with radiometric liquid chromatography and mass spectrometry. The major liver microsome metabolite of PB-93 has the PFT Zn-binding N-methyl-imidazole removed; this metabolite is inactive in blocking PFT function. By solving the X-ray crystal structure of PB-93 bound to rat PFT, a model of PB-93 bound to malarial PFT was constructed. This model suggests areas of the THQ PFTIs that can be modified to retain efficacy and protect the Zn-binding N-methyl-imidazole from dealkylation.


Assuntos
Antimaláricos/farmacologia , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Plasmodium falciparum/enzimologia , Quinolinas/farmacologia , Sulfonamidas/farmacologia , Animais , Antimaláricos/síntese química , Antimaláricos/farmacocinética , Ductos Biliares/metabolismo , Células CACO-2 , Permeabilidade da Membrana Celular/efeitos dos fármacos , Cristalografia por Raios X , Remoção de Radical Alquila , Feminino , Humanos , Malária/tratamento farmacológico , Malária/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Testes de Mutagenicidade , Testes de Sensibilidade Parasitária , Plasmodium berghei/efeitos dos fármacos , Plasmodium falciparum/efeitos dos fármacos , Quinolinas/síntese química , Quinolinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética
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