RESUMEN
Dual inhibitors of bacterial gyrB and parE based on a 5-(2-pyrimidinyl)-imidazo[1,2-a]pyridine template exhibited MICs (microg/mL) of 0.06-64 (Sau), 0.25-64 (MRSA), 0.06-64 (Spy), 0.06-64 (Spn), and 0.03-64 (FQR Spn). Selected examples were efficacious in mouse sepsis and lung infection models at <50mg/kg (PO dosing).
Asunto(s)
Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV/metabolismo , Piridinas/farmacología , Piridinas/uso terapéutico , Animales , Antibacterianos/química , Bacterias Grampositivas/efectos de los fármacos , Imidazoles/química , Imidazoles/farmacología , Imidazoles/uso terapéutico , Pulmón/efectos de los fármacos , Pulmón/microbiología , Ratones , Pruebas de Sensibilidad Microbiana , Piridinas/química , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Ratas , Sepsis/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
Multidrug-resistant Gram-negative pathogens are an emerging threat to human health, and addressing this challenge will require development of new antibacterial agents. This can be achieved through an improved molecular understanding of drug-target interactions combined with enhanced delivery of these agents to the site of action. Herein we describe the first application of siderophore receptor-mediated drug uptake of lactivicin analogues as a strategy that enables the development of novel antibacterial agents against clinically relevant Gram-negative bacteria. We report the first crystal structures of several sideromimic conjugated compounds bound to penicillin binding proteins PBP3 and PBP1a from Pseudomonas aeruginosa and characterize the reactivity of lactivicin and ß-lactam core structures. Results from drug sensitivity studies with ß-lactamase enzymes are presented, as well as a structure-based hypothesis to reduce susceptibility to this enzyme class. Finally, mechanistic studies demonstrating that sideromimic modification alters the drug uptake process are discussed.
Asunto(s)
Bacterias Gramnegativas/metabolismo , Péptidos/metabolismo , Receptores de Superficie Celular/metabolismo , Sideróforos/metabolismo , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Gramnegativas/enzimología , Pruebas de Sensibilidad Microbiana , Péptidos/efectos de los fármacos , Péptidos Cíclicos , beta-Lactamasas/metabolismoRESUMEN
A simple one-pot method for the synthesis of diversely functionalized pyrazoles from aryl nucleophiles, di-tert-butylazodicarboxlate, and 1,3-dicarbonyl or equivalent compounds is presented.
Asunto(s)
Hidrocarburos Halogenados/química , Pirazoles/síntesis química , Catálisis , Técnicas Químicas Combinatorias , Estructura Molecular , Pirazoles/químicaRESUMEN
Low nanomolar corticotropin releasing factor type-1 (CRF(1)) receptor antagonists containing unique indanylamines were identified from the heteroatom-linked pyrazine chemotype. The most potent indanylpyrazine had a K(i)=11+/-1 nM. The oxygen-linked pyrazinyl derivatives were prepared through a copper-catalyzed coupling of a pyridinone to a bromo- or iodopyrazine.