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1.
Antimicrob Agents Chemother ; 65(8): e0050821, 2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34097491

RESUMO

We utilized the rabbit model of aortic valve infective endocarditis to examine the combined efficacy of the lysin LSVT-1701 plus daptomycin. The combination of LSVT-1701 plus daptomycin was highly effective at reducing methicillin-resistant Staphylococcus aureus (MRSA) counts in target tissue. When given for four daily doses, both lysin dose regimens in combination with daptomycin sterilized all target tissues. These findings suggest that LSVT-1701 warrants further clinical evaluation as an adjunctive therapy for the treatment of invasive MRSA infections.


Assuntos
Daptomicina , Endocardite Bacteriana , Endocardite , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Animais , Antibacterianos/uso terapêutico , Daptomicina/uso terapêutico , Endocardite/tratamento farmacológico , Endocardite Bacteriana/tratamento farmacológico , Humanos , Testes de Sensibilidade Microbiana , Coelhos , Infecções Estafilocócicas/tratamento farmacológico
2.
Artigo em Inglês | MEDLINE | ID: mdl-29507073

RESUMO

Cutaneous leishmaniasis (CL) is caused by several species of the protozoan parasite Leishmania, affecting an estimated 10 million people worldwide. Previously reported strategies for the development of topical CL treatments have focused primarily on drug permeation and formulation optimization as the means to increase treatment efficacy. Our approach aims to identify compounds with antileishmanial activity and properties consistent with topical administration. Of the test compounds, five benzoxaboroles showed potent activity (50% effective concentration [EC50] < 5 µM) against intracellular amastigotes of at least one Leishmania species and acceptable activity (20 µM < EC50 < 30 µM) against two more species. Benzoxaborole compounds were further prioritized on the basis of the in vitro evaluation of progression criteria related to skin permeation, such as the partition coefficient and solubility. An MDCKII-hMDR1 cell assay showed overall good permeability and no significant interaction with the P-glycoprotein transporter for all substrates except LSH002 and LSH031. The benzoxaboroles were degraded, to some extent, by skin enzymes but had stability superior to that of para-hydroxybenzoate compounds, which are known skin esterase substrates. Evaluation of permeation through reconstructed human epidermis showed LSH002 to be the most permeant, followed by LSH003 and LSH001. Skin disposition studies following finite drug formulation application to mouse skin demonstrated the highest permeation for LSH001, followed by LSH003 and LSH002, with a significantly larger amount of LSH001 than the other compounds being retained in skin. Finally, the efficacy of the leads (LSH001, LSH002, and LSH003) against Leishmania major was tested in vivo LSH001 suppressed lesion growth upon topical application, and LSH003 reduced the lesion size following oral administration.


Assuntos
Antiprotozoários/farmacocinética , Antiprotozoários/uso terapêutico , Leishmaniose Cutânea/tratamento farmacológico , Administração Oral , Administração Tópica , Antiprotozoários/administração & dosagem , Compostos de Boro/administração & dosagem , Compostos de Boro/farmacocinética , Compostos de Boro/uso terapêutico , Leishmaniose Cutânea/parasitologia
3.
Bioorg Med Chem Lett ; 28(2): 207-213, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29191556

RESUMO

A 900 compound nitroimidazole-based library derived from our pretomanid backup program with TB Alliance was screened for utility against human African trypanosomiasis (HAT) by the Drugs for Neglected Diseases initiative. Potent hits included 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides, which surprisingly displayed good metabolic stability and excellent cell permeability. Following comprehensive mouse pharmacokinetic assessments on four hits and determination of the most active chiral form, a thiazine oxide counterpart of pretomanid (24) was identified as the best lead. With once daily oral dosing, this compound delivered complete cures in an acute infection mouse model of HAT and increased survival times in a stage 2 model, implying the need for more prolonged CNS exposure. In preliminary SAR findings, antitrypanosomal activity was reduced by removal of the benzylic methylene but enhanced through a phenylpyridine-based side chain, providing important direction for future studies.


Assuntos
Nitroimidazóis/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Tripanossomíase Africana/tratamento farmacológico , Administração Oral , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Nitroimidazóis/administração & dosagem , Nitroimidazóis/química , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
4.
Parasitology ; 141(1): 104-18, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24007596

RESUMO

SUMMARY This review presents a progression strategy for the discovery of new anti-parasitic drugs that uses in vitro susceptibility, time-kill and reversibility measures to define the therapeutically relevant exposure required in target tissues of animal infection models. The strategy is exemplified by the discovery of SCYX-7158 as a potential oral treatment for stage 2 (CNS) Human African Trypanosomiasis (HAT). A critique of current treatments for stage 2 HAT is included to provide context for the challenges of achieving target tissue disposition and the need for establishing pharmacokinetic-pharmacodynamic (PK-PD) measures early in the discovery paradigm. The strategy comprises 3 stages. Initially, compounds demonstrating promising in vitro activity and selectivity for the target organism over mammalian cells are advanced to in vitro metabolic stability, barrier permeability and tissue binding assays to establish that they will likely achieve and maintain therapeutic concentrations during in-life efficacy studies. Secondly, in vitro time-kill and reversibility kinetics are employed to correlate exposure (based on unbound concentrations) with in vitro activity, and to identify pharmacodynamic measures that would best predict efficacy. Lastly, this information is used to design dosing regimens for pivotal pharmacokinetic-pharmacodyamic studies in animal infection models.


Assuntos
Benzamidas/farmacocinética , Compostos de Boro/farmacocinética , Tripanossomicidas/farmacocinética , Trypanosoma brucei gambiense/efeitos dos fármacos , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Administração Oral , Animais , Área Sob a Curva , Benzamidas/administração & dosagem , Benzamidas/sangue , Bioensaio , Barreira Hematoencefálica/efeitos dos fármacos , Compostos de Boro/administração & dosagem , Compostos de Boro/sangue , Permeabilidade Capilar , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Tripanossomicidas/administração & dosagem , Tripanossomicidas/sangue , Trypanosoma brucei gambiense/crescimento & desenvolvimento , Trypanosoma brucei rhodesiense/crescimento & desenvolvimento , Tripanossomíase Africana/sangue , Tripanossomíase Africana/parasitologia
5.
Bioorg Med Chem Lett ; 21(10): 2816-9, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21507639

RESUMO

A series of 2,4-diaminopyrimidines was investigated and compounds were found to have in vivo efficacy against Trypanosoma brucei in an acute mouse model. However, in vitro permeability data suggested the 2,4-diaminopyrimidenes would have poor permeability through the blood brain barrier. Consequently a series of 4-desamino analogs were synthesized and found to have improved in vitro permeability.


Assuntos
Pirimidinas/síntese química , Pirimidinas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Aminas/química , Animais , Barreira Hematoencefálica , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Permeabilidade , Pirimidinas/química , Relação Quantitativa Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/química
6.
Diagn Microbiol Infect Dis ; 101(3): 115471, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34280671

RESUMO

LSVT-1701 (previously known as SAL200), is a novel, recombinantly-produced, bacteriophage-encoded lysin that specifically targets staphylococci via cell wall enzymatic hydrolysis. In vitro activities of LSVT-1701 and comparators were tested against 415 Staphylococcus aureus and coagulase-negative staphylococci (CoNS) clinical isolates expressing various resistance phenotypes. The isolates were collected worldwide from 2002 to 2019 and tested for in vitro susceptibility using broth microdilution methodology performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Minimum inhibitory concentration (MIC) interpretations were based on CLSI and EUCAST criteria. MIC90 for all S. aureus, methicillin-susceptible S. aureus, methicillin-resistant S. aureus, and CoNS, were 2, 2, 2 and 2 µg/ml, respectively. LSVT-1701's activity was not adversely affected by resistance to antimicrobial comparators against this worldwide collection of S. aureus and CoNS clinical isolates. The results of this study support further clinical development of LSVT-1701 to treat staphylococcal infections, including those caused by multidrug resistance isolates.


Assuntos
Antibacterianos/farmacologia , Coagulase/análise , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus/efeitos dos fármacos , Humanos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Staphylococcus/classificação
7.
Antimicrob Agents Chemother ; 54(10): 4379-88, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20660666

RESUMO

We report the discovery of novel boron-containing molecules, exemplified by N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-trifluoromethylbenzamide (AN3520) and 4-fluoro-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-2-trifluoromethylbenzamide (SCYX-6759), as potent compounds against Trypanosoma brucei in vitro, including the two subspecies responsible for human disease T. b. rhodesiense and T. b. gambiense. These oxaborole carboxamides cured stage 1 (hemolymphatic) trypanosomiasis infection in mice when administered orally at 2.5 to 10 mg/kg of body weight for 4 consecutive days. In stage 2 disease (central nervous system [CNS] involvement), mice infected with T. b. brucei were cured when AN3520 or SCYX-6759 were administered intraperitoneally or orally (50 mg/kg) twice daily for 7 days. Oxaborole-treated animals did not exhibit gross signs of compound-related acute or subchronic toxicity. Metabolism and pharmacokinetic studies in several species, including nonhuman primates, demonstrate that both SCYX-6759 and AN3520 are low-clearance compounds. Both compounds were well absorbed following oral dosing in multiple species and also demonstrated the ability to cross the blood-brain barrier with no evidence of interaction with the P-glycoprotein transporter. Overall, SCYX-6759 demonstrated superior pharmacokinetics, and this was reflected in better efficacy against stage 2 disease in the mouse model. On the whole, oxaboroles demonstrate potent activity against all T. brucei subspecies, excellent physicochemical profiles, in vitro metabolic stability, a low potential for CYP450 inhibition, a lack of active efflux by the P-glycoprotein transporter, and high permeability. These properties strongly suggest that these novel chemical entities are suitable leads for the development of new and effective orally administered treatments for human African trypanosomiasis.


Assuntos
Imidazóis/uso terapêutico , Tripanossomicidas/uso terapêutico , Trypanosoma brucei brucei/patogenicidade , Tripanossomíase Africana/tratamento farmacológico , Animais , Feminino , Humanos , Imidazóis/química , Macaca fascicularis , Masculino , Camundongos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Trypanosoma brucei brucei/efeitos dos fármacos
8.
Future Med Chem ; 3(10): 1259-78, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21859301

RESUMO

Human African trypanosomiasis, caused by the kinetoplastid parasite Trypanosoma brucei, affects thousands of people across sub-Saharan Africa, and is fatal if left untreated. Treatment options for this disease, particularly stage 2 disease, which occurs after parasites have infected brain tissue, are limited due to inadequate efficacy, toxicity and the complexity of treatment regimens. We have discovered and optimized a series of benzoxaborole-6-carboxamides to provide trypanocidal compounds that are orally active in murine models of human African trypanosomiasis. A key feature of this series is the presence of a boron atom in the heterocyclic core structure, which is essential to the observed trypanocidal activity. We also report the in vivo pharmacokinetic properties of lead compounds from the series and selection of SCYX-7158 as a preclinical candidate.


Assuntos
Antiprotozoários/química , Benzoxazóis/química , Tripanossomíase Africana/tratamento farmacológico , Administração Oral , Animais , Antiprotozoários/farmacocinética , Antiprotozoários/uso terapêutico , Benzamidas/química , Benzamidas/farmacocinética , Benzamidas/uso terapêutico , Benzoxazóis/farmacocinética , Benzoxazóis/uso terapêutico , Compostos de Boro/química , Compostos de Boro/farmacocinética , Compostos de Boro/uso terapêutico , Encéfalo/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Camundongos , Relação Estrutura-Atividade , Trypanosoma brucei brucei/isolamento & purificação
9.
PLoS Negl Trop Dis ; 5(6): e1151, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21738803

RESUMO

BACKGROUND: Human African trypanosomiasis (HAT) is an important public health problem in sub-Saharan Africa, affecting hundreds of thousands of individuals. An urgent need exists for the discovery and development of new, safe, and effective drugs to treat HAT, as existing therapies suffer from poor safety profiles, difficult treatment regimens, limited effectiveness, and a high cost of goods. We have discovered and optimized a novel class of small-molecule boron-containing compounds, benzoxaboroles, to identify SCYX-7158 as an effective, safe and orally active treatment for HAT. METHODOLOGY/PRINCIPAL FINDINGS: A drug discovery project employing integrated biological screening, medicinal chemistry and pharmacokinetic characterization identified SCYX-7158 as an optimized analog, as it is active in vitro against relevant strains of Trypanosoma brucei, including T. b. rhodesiense and T. b. gambiense, is efficacious in both stage 1 and stage 2 murine HAT models and has physicochemical and in vitro absorption, distribution, metabolism, elimination and toxicology (ADMET) properties consistent with the compound being orally available, metabolically stable and CNS permeable. In a murine stage 2 study, SCYX-7158 is effective orally at doses as low as 12.5 mg/kg (QD×7 days). In vivo pharmacokinetic characterization of SCYX-7158 demonstrates that the compound is highly bioavailable in rodents and non-human primates, has low intravenous plasma clearance and has a 24-h elimination half-life and a volume of distribution that indicate good tissue distribution. Most importantly, in rodents brain exposure of SCYX-7158 is high, with C(max) >10 µg/mL and AUC(0-24 hr) >100 µg*h/mL following a 25 mg/kg oral dose. Furthermore, SCYX-7158 readily distributes into cerebrospinal fluid to achieve therapeutically relevant concentrations in this compartment. CONCLUSIONS/SIGNIFICANCE: The biological and pharmacokinetic properties of SCYX-7158 suggest that this compound will be efficacious and safe to treat stage 2 HAT. SCYX-7158 has been selected to enter preclinical studies, with expected progression to phase 1 clinical trials in 2011.


Assuntos
Antiprotozoários/administração & dosagem , Antiprotozoários/farmacocinética , Benzamidas/administração & dosagem , Benzamidas/farmacocinética , Compostos de Boro/administração & dosagem , Compostos de Boro/farmacocinética , Tripanossomíase Africana/tratamento farmacológico , Administração Oral , Animais , Antiprotozoários/efeitos adversos , Benzamidas/efeitos adversos , Compostos de Boro/efeitos adversos , Modelos Animais de Doenças , Feminino , Camundongos , Testes de Sensibilidade Parasitária , Doenças dos Primatas/tratamento farmacológico , Primatas , Doenças dos Roedores/tratamento farmacológico , Resultado do Tratamento , Trypanosoma/efeitos dos fármacos
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