RESUMO
A successful scaffold-hopping approach gave a novel series of inhibitors of bacterial glutamate racemase (MurI). Early SAR studies of the 8-benzyl pteridine-6,7-diones led to compounds with micromolar enzyme potency and antibacterial activity.
Assuntos
Isomerases de Aminoácido/antagonistas & inibidores , Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias Gram-Positivas/enzimologia , Pteridinas/síntese química , Pteridinas/farmacologia , Antibacterianos/química , Técnicas de Química Combinatória , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pteridinas/química , Relação Estrutura-AtividadeRESUMO
An early SAR study of a screening hit series has generated a series of 9-benzyl purines as inhibitors of bacterial glutamate racemase (MurI) with micromolar enzyme potency and improved physical properties. X-ray co-crystal EI structures were obtained.
Assuntos
Isomerases de Aminoácido/antagonistas & inibidores , Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias Gram-Positivas/enzimologia , Purinas/síntese química , Purinas/farmacologia , Antibacterianos/química , Técnicas de Química Combinatória , Cristalografia por Raios X , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/genética , Enterococcus faecium/efeitos dos fármacos , Enterococcus faecium/genética , Bactérias Gram-Positivas/genética , Conformação Molecular , Estrutura Molecular , Purinas/química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/genética , Relação Estrutura-AtividadeRESUMO
Fatty acid biosynthesis is essential to bacterial growth in Gram-negative pathogens. Several small molecules identified through a combination of high-throughput and fragment screening were cocrystallized with FabH (ß-ketoacyl-acyl carrier protein synthase III) from Escherichia coli and Streptococcus pneumoniae. Structure-based drug design was used to merge several scaffolds to provide a new class of inhibitors. After optimization for Gram-negative enzyme inhibitory potency, several compounds demonstrated antimicrobial activity against an efflux-negative strain of Haemophilus influenzae. Mutants resistant to these compounds had mutations in the FabH gene near the catalytic triad, validating FabH as a target for antimicrobial drug discovery.
Assuntos
3-Oxoacil-(Proteína de Transporte de Acila) Sintase/antagonistas & inibidores , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Farmacorresistência Bacteriana , Inibidores Enzimáticos/farmacologia , Haemophilus influenzae/enzimologia , 3-Oxoacil-(Proteína de Transporte de Acila) Sintase/química , 3-Oxoacil-(Proteína de Transporte de Acila) Sintase/genética , 3-Oxoacil-(Proteína de Transporte de Acila) Sintase/metabolismo , Antibacterianos/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Desenho de Fármacos , Inibidores Enzimáticos/química , Infecções por Haemophilus/microbiologia , Haemophilus influenzae/química , Haemophilus influenzae/efeitos dos fármacos , Haemophilus influenzae/genética , Humanos , Testes de Sensibilidade Microbiana , MutaçãoRESUMO
Novel non-fluoroquinolone inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) are of interest for the development of new antibacterial agents that are not impacted by target-mediated cross-resistance with fluoroquinolones. Aminopiperidines that have a bicyclic aromatic moiety linked through a carbon to an ethyl bridge, such as 1, generally show potent broad-spectrum antibacterial activity, including quinolone-resistant isolates, but suffer from potent hERG inhibition (IC(50)= 3 µM for 1). We now disclose the finding that new analogues of 1 with an N-linked cyclic amide moiety attached to the ethyl bridge, such as 24m, retain the broad-spectrum antibacterial activity of 1 but show significantly less hERG inhibition (IC(50)= 31 µM for 24m) and higher free fraction than 1. One optimized analogue, compound 24l, showed moderate clearance in the dog and promising efficacy against Staphylococcus aureus in a mouse thigh infection model.
Assuntos
Antibacterianos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , DNA Topoisomerases Tipo II/metabolismo , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Piperidinas/síntese química , Inibidores da Topoisomerase/síntese química , Animais , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Cães , Farmacorresistência Bacteriana , Canal de Potássio ERG1 , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Piperidinas/farmacocinética , Piperidinas/farmacologia , Conformação Proteica , Ratos , Infecções Estafilocócicas/tratamento farmacológico , Relação Estrutura-Atividade , Inibidores da Topoisomerase/farmacocinética , Inibidores da Topoisomerase/farmacologiaRESUMO
The advent of template-directed synthesis has provided access to a range of new interlocked molecular architectures. Although many syntheses of molecular catenanes and rotaxanes have been reported, molecular knots are a class of molecules with topologically non-planar graphs that are rather rare. Here we report a synthetic strategy for the preparation of a molecular trefoil knot from a flexible bipyridine oligomer and a zinc(II) octahedral coordination template. The oligomer folds into a stable open-knot conformation in the presence of the template, and trapping of this arrangement through esterification or ring-closing metathesis produces the closed-knot complex. Subsequent removal of the template from the metathesis product results in a molecular trefoil knot.
RESUMO
Using a high-throughput screening campaign, we identified the 4,6-bis anilino pyrimidines as inhibitors of the cyclin-dependent kinase, CDK4. Herein we describe the further chemical modification and use of X-ray crystallography to develop potent and selective in vitro inhibitors of CDK4.
Assuntos
Antineoplásicos/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Proteínas Proto-Oncogênicas , Pirimidinas/farmacologia , Animais , Antineoplásicos/síntese química , Sítios de Ligação , Cristalografia por Raios X , Quinase 4 Dependente de Ciclina , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Pirimidinas/síntese química , Relação Estrutura-AtividadeRESUMO
Through chemical modification and X-ray crystallography we identified the 2,4-bis anilino pyrimidines as potent inhibitors of CDK4. Herein, we describe the optimisation of this series.
Assuntos
Antineoplásicos/farmacologia , Quinases Ciclina-Dependentes/antagonistas & inibidores , Proteínas Proto-Oncogênicas , Pirimidinas/farmacologia , Trifosfato de Adenosina/química , Animais , Antineoplásicos/síntese química , Sítios de Ligação , Cristalografia por Raios X , Quinase 4 Dependente de Ciclina , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Pirimidinas/síntese química , Relação Estrutura-AtividadeRESUMO
High-throughput screening identified the imidazo[1,2-a]pyridine and bisanilinopyrimidine series as inhibitors of the cyclin-dependent kinase CDK4. Comparison of their experimentally-determined binding modes and emerging structure-activity trends led to the development of potent and selective imidazo[1,2-a]pyridine inhibitors for CDK4 and in particular CDK2.