RESUMO
Novel bacterial type II topoisomerase inhibitors (NBTIs) constitute a promising new class of antibacterial agents. We report a series of NBTIs with potent anti-staphylococcal activity and diminished hERG inhibition. Dioxane-linked compound 9 demonstrated MICs ≤1⯵g/mL against both methicillin-susceptible (MSSA) and -resistant Staphylococcus aureus (MRSA), accompanied by reduced hERG inhibition as compared to cyclohexane- or piperidine-linked analogs.
Assuntos
Antibacterianos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Dioxanos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Quinolinas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Cristalografia por Raios X , Dioxanos/química , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Staphylococcus aureus Resistente à Meticilina/enzimologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/químicaRESUMO
The previously accepted structure of the marine toxin azaspiracid-3 is revised based upon an original convergent and stereoselective total synthesis of the natural product. The development of a structural revision hypothesis, its testing, and corroboration are reported. Synthetic (6R,10R,13R,14R,16R,17R,19S,20S,21R,24S,25S,28S,30S,32R, 33R,34R,36S,37S,39R)-azaspiracid-3 chromatographically and spectroscopically matched naturally occurring azaspiracid-3, whereas the previously assigned 20R epimer did not.
Assuntos
Produtos Biológicos/química , Produtos Biológicos/síntese química , Furanos/química , Furanos/síntese química , Piranos/química , Piranos/síntese química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Cromatografia Líquida , Espectrometria de Massas , Estrutura Molecular , Oxirredução , Espectroscopia de Prótons por Ressonância Magnética , EstereoisomerismoRESUMO
A convergent and stereoselective total synthesis of the previously assigned structure of azaspiracid-3 has been achieved by a late-stage Nozaki-Hiyama-Kishi coupling to form the C21-C22 bond with the C20 configuration unambiguously established from l-(+)-tartaric acid. Postcoupling steps involved oxidation to an ynone, modified Stryker reduction of the alkyne, global deprotection, and oxidation of the resulting C1 primary alcohol to the carboxylic acid. The synthetic product matched naturally occurring azaspiracid-3 by mass spectrometry, but differed both chromatographically and spectroscopically.
Assuntos
Produtos Biológicos/química , Furanos/síntese química , Piranos/síntese química , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Cromatografia Líquida , Furanos/química , Estrutura Molecular , Oxirredução , Espectroscopia de Prótons por Ressonância Magnética , Piranos/química , Estereoisomerismo , Espectrometria de Massas em TandemRESUMO
Novel bacterial topoisomerase inhibitors (NBTIs) are among the most promising new antibiotics in preclinical/clinical development. We previously reported dioxane-linked NBTIs with potent antistaphylococcal activity and reduced hERG inhibition, a key safety liability. Herein, polarity-focused optimization enabled the delineation of clear structure-property relationships for both microsomal metabolic stability and hERG inhibition, resulting in the identification of lead compound 79. This molecule demonstrates potent antibacterial activity against diverse Gram-positive pathogens, inhibition of both DNA gyrase and topoisomerase IV, a low frequency of resistance, a favorable in vitro cardiovascular safety profile, and in vivo efficacy in a murine model of methicillin-resistant Staphylococcus aureus infection.
Assuntos
Antibacterianos/farmacologia , Dioxanos/farmacologia , Inibidores Enzimáticos/farmacologia , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , DNA Girase/metabolismo , DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/metabolismo , Dioxanos/síntese química , Dioxanos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of Novel Bacterial Topoisomerase Inhibitors (NBTIs) employing a linker derived from isomannide were synthesized and evaluated. Reduced hERG inhibition was observed compared to structure-matched analogues with different linkers, and compound 6 showed minimal proarrhythmic potential using an in vitro panel of cardiac ion channels. Compound 6 also displayed excellent activity against fluoroquinolone-resistant MRSA (MIC90 = 2 µg/mL) and other Gram-positive pathogens.
Assuntos
Antibacterianos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Inibidores da Topoisomerase/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/químicaRESUMO
Azaspiracid-34 (AZA34) is a recently described structurally unique member of the azaspiracid class of marine neurotoxins. Its novel structure, tentatively assigned on the basis of MS and 1H NMR spectroscopy, is accompanied by a 5.5-fold higher level of toxicity against Jurkat T lymphocytes than AZA1. To completely assign the structure of AZA34 and provide material for in-depth biological evaluation and detection, synthetic access to AZA34 was targeted. This began with the convergent and stereoselective assembly of the C1-C19 domain of AZA34 designed to dovetail with the recent total synthesis approach to AZA3.
Assuntos
Células Jurkat/citologia , Toxinas Marinhas/toxicidade , Neurotoxinas/toxicidade , Compostos de Espiro/síntese química , Humanos , Células Jurkat/química , Espectroscopia de Ressonância Magnética , Toxinas Marinhas/síntese química , Toxinas Marinhas/química , Estrutura Molecular , Compostos de Espiro/químicaRESUMO
The development of new therapies to treat methicillin-resistant Staphylococcus aureus (MRSA) is needed to counteract the significant threat that MRSA presents to human health. Novel inhibitors of DNA gyrase and topoisomerase IV (TopoIV) constitute one highly promising approach, but continued optimization is required to realize the full potential of this class of antibiotics. Herein, we report further studies on a series of dioxane-linked derivatives, demonstrating improved antistaphylococcal activity and reduced hERG inhibition. A subseries of analogues also possesses enhanced inhibition of the secondary target, TopoIV.
Assuntos
Antibacterianos/síntese química , DNA Girase/metabolismo , Dioxanos/química , Staphylococcus aureus Resistente à Meticilina/enzimologia , Inibidores da Topoisomerase/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Sítios de Ligação , DNA Girase/química , DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/química , DNA Topoisomerase IV/metabolismo , Regulação para Baixo , Canal de Potássio ERG1/metabolismo , Humanos , Células K562 , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Inibidores da Topoisomerase/química , Inibidores da Topoisomerase/farmacologiaRESUMO
An efficient synthesis of the C22-C40 domain of the azaspiracids is described. The synthetic route features a Nozaki-Hiyama-Kishi (NHK) coupling and chelation controlled Mukaiyama aldol reaction to access an acyclic intermediate and a double-intramolecular-hetero-Michael addition (DIHMA) to provide the FG-ring system bridged ketal.