RESUMO
In 2013, the Centers for Disease Control highlighted Clostridium difficile as an urgent threat for antibiotic-resistant infections, in part due to the emergence of highly virulent fluoroquinolone-resistant strains. Limited therapeutic options currently exist, many of which result in disease relapse. We sought to identify molecules specifically targeting C. difficile in high-throughput screens of our diversity-oriented synthesis compound collection. We identified two scaffolds with apparently novel mechanisms of action that selectively target C. difficile while having little to no activity against other intestinal anaerobes; preliminary evidence suggests that compounds from one of these scaffolds target the glutamate racemase. In vivo efficacy data suggest that both compound series may provide lead optimization candidates.
Assuntos
Isomerases de Aminoácido/antagonistas & inibidores , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Clostridioides difficile/efeitos dos fármacos , Enterocolite Pseudomembranosa/tratamento farmacológico , Compostos Heterocíclicos com 2 Anéis/farmacologia , Compostos de Fenilureia/farmacologia , Pirróis/farmacologia , Quinolinas/farmacologia , Isomerases de Aminoácido/genética , Isomerases de Aminoácido/metabolismo , Animais , Antibacterianos/síntese química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Clostridioides difficile/enzimologia , Clostridioides difficile/genética , Clostridioides difficile/crescimento & desenvolvimento , Desenho de Fármacos , Enterocolite Pseudomembranosa/microbiologia , Enterocolite Pseudomembranosa/mortalidade , Enterocolite Pseudomembranosa/patologia , Feminino , Expressão Gênica , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/crescimento & desenvolvimento , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/crescimento & desenvolvimento , Compostos Heterocíclicos com 2 Anéis/síntese química , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Compostos de Fenilureia/síntese química , Pirróis/síntese química , Quinolinas/síntese química , Especificidade da Espécie , Relação Estrutura-Atividade , Análise de SobrevidaRESUMO
Comprehensive SAR studies were undertaken in the 3,4-diaminocyclobut-3-ene-1,2-dione class of CXCR2/CXCR1 receptor antagonists to explore the role of the heterocycle on chemokine receptor binding affinities, functional activity, as well as oral exposure in rat. The nature of the heterocycle as well as the requisite substitution pattern around the heterocycle was shown to have a dramatic effect on the overall biological profile of this class of compounds. The furyl class, particularly the 4-halo adducts, was found to possess superior binding affinities for both the CXCR2 and CXCR1 receptors, functional activity, as well as oral exposure in rat versus other heterocyclic derivatives.
Assuntos
Ciclobutanos/química , Ciclobutanos/farmacologia , Diaminas/química , Diaminas/farmacologia , Receptores de Interleucina-8A/antagonistas & inibidores , Receptores de Interleucina-8B/antagonistas & inibidores , Animais , Linhagem Celular , Ciclobutanos/síntese química , Diaminas/síntese química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Camundongos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of 3,4- and 3,5-disubstituted phenyl-containing cyclobutenedione analogues were synthesized and evaluated as CXCR2 receptor antagonists. Variations in the disubstitution pattern of the phenyl ring afforded new compounds with potent CXCR2 binding affinity in the low nanomolar ranges. Moreover, two potent compounds 19 and 26 exhibited good oral pharmacokinetic profiles.
