RESUMO
We report here the optimization of an HldE kinase inhibitor to low nanomolar potency, which resulted in the identification of the first reported compounds active on selected E. coli strains. One of the most interesting candidates, compound 86, was shown to inhibit specifically bacterial LPS heptosylation on efflux pump deleted E. coli strains. This compound did not interfere with E. coli bacterial growth (MIC > 32 µg/mL) but sensitized this pathogen to hydrophobic antibiotics like macrolides normally inactive on Gram-negative bacteria. In addition, 86 could sensitize E. coli to serum complement killing. These results demonstrate that HldE kinase is a suitable target for drug discovery. They also pave the way toward novel possibilities of treating or preventing bloodstream infections caused by pathogenic Gram negative bacteria by inhibiting specific virulence factors.
Assuntos
Antibacterianos/síntese química , Benzotiazóis/síntese química , Escherichia coli/efeitos dos fármacos , Complexos Multienzimáticos/antagonistas & inibidores , Nucleotidiltransferases/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Triazinas/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Benzotiazóis/química , Benzotiazóis/farmacologia , Escherichia coli/patogenicidade , Lipopolissacarídeos/farmacologia , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Triazinas/química , Triazinas/farmacologia , Virulência/efeitos dos fármacosRESUMO
In this paper, we present some elements of our optimization program to decouple triclosan's specific FabI effect from its nonspecific cytotoxic component. The implementation of this strategy delivered highly specific, potent, and nonbiocidal new FabI inhibitors. We also disclose some preclinical data of one of their representatives, 83, a novel antibacterial compound active against resistant staphylococci and some clinically relevant Gram negative bacteria that is currently undergoing clinical trials.
Assuntos
Anti-Infecciosos Locais/farmacologia , Benzamidas/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/antagonistas & inibidores , Bactérias Gram-Negativas/efeitos dos fármacos , Éteres Fenílicos/farmacologia , Triclosan/farmacologia , Animais , Anti-Infecciosos Locais/síntese química , Benzamidas/síntese química , Células Cultivadas , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Éteres Fenílicos/síntese química , Ratos , Relação Estrutura-Atividade , Triclosan/síntese químicaRESUMO
[reaction: see text] Oxidation of alkyl and cycloalkyl arenes with tert-butyl hydroperoxide catalyzed by bismuth and picolinic acid in pyridine and acetic acid gave the corresponding benzylic ketones (48-99%). Alternatively, oxidation of methyl arenes gave the corresponding substituted benzoic acids (50-95%). Preliminary mechanistic studies were consistent with a radical mechanism rather than a bismuth(III)-bismuth(V) cycle.
Assuntos
Compostos de Benzil/química , Bismuto/química , terc-Butil Hidroperóxido/química , Catálise , Ligação de Hidrogênio , Estrutura Molecular , OxirreduçãoRESUMO
[reaction: see text] Ugi reaction between an (S)-alpha-amino acid, an aromatic aldehyde, and an isonitrile proceeds best under catalysis by TiCl(4) in MeOH. The sense of diastereoinduction is (S,S).