RESUMEN
The synthesis and biological activity of a new series of LpxC inhibitors represented by pyridone methylsulfone hydroxamate 2a is presented. Members of this series have improved solubility and free fraction when compared to compounds in the previously described biphenyl methylsulfone hydroxamate series, and they maintain superior Gram-negative antibacterial activity to comparator agents.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/síntesis química , Bacterias Gramnegativas/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Ácidos Hidroxámicos/síntesis química , Piridonas/síntesis química , Ácidos Sulfónicos/síntesis química , Animales , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Cristalografía por Rayos X , Humanos , Ácidos Hidroxámicos/farmacocinética , Ácidos Hidroxámicos/farmacología , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/enzimología , Piridonas/farmacocinética , Piridonas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Ácidos Sulfónicos/farmacocinética , Ácidos Sulfónicos/farmacologíaRESUMEN
In this paper, we present the synthesis and SAR as well as selectivity, pharmacokinetic, and infection model data for representative analogues of a novel series of potent antibacterial LpxC inhibitors represented by hydroxamic acid.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Antibacterianos/síntesis química , Compuestos de Bifenilo/síntesis química , Ácidos Hidroxámicos/síntesis química , Éteres Fenílicos/síntesis química , Infecciones por Pseudomonas/tratamiento farmacológico , Sulfuros/síntesis química , Sulfonas/síntesis química , Animales , Antibacterianos/química , Antibacterianos/farmacología , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Dominio Catalítico , Cristalografía por Rayos X , Farmacorresistencia Bacteriana , Enlace de Hidrógeno , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Ratones , Modelos Moleculares , Conformación Molecular , Éteres Fenílicos/química , Éteres Fenílicos/farmacología , Pseudomonas aeruginosa , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Sulfuros/química , Sulfuros/farmacología , Sulfonas/química , Sulfonas/farmacologíaRESUMEN
Heteroaryl isothiazolones (HITZs) are antibacterial agents that display excellent in vitro activity against Staphylococcus aureus. We recently identified a series of these compounds that show potent bactericidal activities against methicillin-resistant Staphylococcus aureus (MRSA). We report here the results of in vitro resistance studies that reveal potential underlying mechanisms of action. HITZs selected gyrA mutations exclusively in first-step mutants of wild-type S. aureus, indicating that in contrast to the case with most quinolones, DNA gyrase is the primary target. The compounds displayed low mutation frequencies (10(-9) to 10(-10)) at concentrations close to the MICs and maintained low MICs (< or =0.016 microg/ml) against mutants with single mutations in either gyrA or grlA (parC). These data suggested that HITZs possess significant inhibitory activities against target enzymes, DNA gyrase and topoisomerase IV. This dual-target inhibition was supported by low 50% inhibitory concentrations against topoisomerase IV as measured in a decatenation activity assay and against DNA gyrase as measured in a supercoiling activity assay. Good antibacterial activities (< or =1 microg/ml) against staphylococcal gyrA grlA double mutants, as well as low frequencies (10(-9) to 10(-10)) of selection of still higher-level mutants, also suggested that HITZs remained active against mutant enzymes. We further demonstrated that HITZs exhibit good inhibition of both S. aureus mutant enzymes and thus continue to possess a novel dual-targeting mode of action against these mutant strains. In stepwise acquisition of mutations, HITZs selected quinolone resistance determining region mutations gyrA(Ser84Leu), grlA(Ser80Phe), grlA(Ala116Val), and gyrA(Glu88Lys) sequentially, suggesting that the corresponding amino acids are key amino acids involved in the binding of HITZs to topoisomerases. The overall profile of these compounds suggests the potential utility of HITZs in combating infections caused by S. aureus, including multidrug-resistant MRSA.
Asunto(s)
Antibacterianos/farmacología , Topoisomerasa de ADN IV/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Staphylococcus aureus/efectos de los fármacos , Inhibidores de Topoisomerasa II , Antibacterianos/química , Girasa de ADN/genética , Farmacorresistencia Bacteriana/efectos de los fármacos , Farmacorresistencia Bacteriana/genética , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mutación , Quinolonas/farmacología , Staphylococcus aureus/enzimología , Staphylococcus aureus/genética , Staphylococcus aureus/aislamiento & purificación , Tiazoles/farmacologíaRESUMEN
Bacterial primase is essential for DNA replication in Gram-positive and Gram-negative bacteria. It is also structurally distinct from eukaryotic primases, and therefore an attractive, but under-explored, target for therapeutic intervention. We applied virtual screening to discover primase inhibitors, and subsequently several commercially available analogs of these initial hits showed potent primase inhibition and in vitro antibacterial activity. This work provides a 3D pharmacophore for primase ligands, SAR trends, and leads that can be further optimized.
Asunto(s)
Antibacterianos/farmacología , ADN Primasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Escherichia coli/enzimología , Antibacterianos/química , ADN Primasa/fisiología , Replicación del ADN/efectos de los fármacos , Diseño de Fármacos , Inhibidores Enzimáticos/química , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Peso MolecularRESUMEN
We describe the biological evaluation of isothiazoloquinolones (ITQs) having structural modifications at the 6-, 7-, and 8-positions. Addition of a methoxy substituent to C-8 effected an increase in antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and a decrease in cytotoxic activity against Hep2 cells. Removal of fluorine from C-6 or replacement of the C-8 carbon with a nitrogen compromised anti-MRSA activity. When the groups attached at C-7 were compared, the anti-MRSA activity decreased in the order 6-isoquinolinyl > 4-pyridinyl > 5-dihydroisoindolyl > 6-tetrahydroisoquinolinyl. The compound with the most desirable in vitro biological profile was 9-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpyridin-4-yl)-9H-isothiazolo[5,4-b]quinoline-3,4-dione (7g). This ITQ demonstrated (i) strong in vitro anti-MRSA activity (MIC90 = 0.5 microg/mL), (ii) strong inhibitory activities against S. aureus DNA gyrase and topoisomerase IV, with weak activity against human topoisomerase II, (iii) weak cytotoxic activities against three cell lines, and (iv) efficacy in an in vivo murine thigh model of infection employing MRSA.
Asunto(s)
Antibacterianos/síntesis química , Quinolonas/síntesis química , Staphylococcus aureus/efectos de los fármacos , Tiazoles/síntesis química , Animales , Antibacterianos/química , Antibacterianos/farmacología , Línea Celular Tumoral , Farmacorresistencia Bacteriana Múltiple , Femenino , Humanos , Resistencia a la Meticilina , Ratones , Quinolonas/química , Quinolonas/farmacología , Staphylococcus aureus/enzimología , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacología , Inhibidores de Topoisomerasa IIRESUMEN
The activities of several tricyclic heteroaryl isothiazolones (HITZs) against an assortment of gram-positive and gram-negative clinical isolates were assessed. These compounds target bacterial DNA replication and were found to possess broad-spectrum activities especially against gram-positive strains, including antibiotic-resistant staphylococci and streptococci. These included methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-nonsusceptible staphylococci, and quinolone-resistant strains. The HITZs were more active than the comparator antimicrobials in most cases. For gram-negative bacteria, the tested compounds were less active against members of the family Enterobacteriaceae but showed exceptional potencies against Haemophilus influenzae, Moraxella catarrhalis, and Neisseria spp. Good activity against several anaerobes, as well as Legionella pneumophila and Mycoplasma pneumoniae, was also observed. Excellent bactericidal activity against staphylococci was observed in time-kill assays, with an approximately 3-log drop in the numbers of CFU/ml occurring after 4 h of exposure to compound. Postantibiotic effects (PAEs) of 2.0 and 1.7 h for methicillin-susceptible S. aureus and MRSA strains, respectively, were observed, and these were similar to those seen with moxifloxacin at 10x MIC. In vivo efficacy was demonstrated in murine infections by using sepsis and thigh infection models. The 50% protective doses were Asunto(s)
Antiinfecciosos/farmacología
, Bacterias Grampositivas/efectos de los fármacos
, Animales
, Farmacorresistencia Bacteriana
, Infecciones por Bacterias Grampositivas/tratamiento farmacológico
, Ratones
, Pruebas de Sensibilidad Microbiana
, Quinolonas/farmacología
, Tiazoles/farmacología
RESUMEN
We synthesized a diverse series of 9H-isothiazolo[5,4-b]quinoline-3,4-diones containing heteroaromatic groups at the 7-position via palladium-catalyzed cross-coupling. Many of these compounds demonstrated potent antistaphylococcal activity (MICs 2 microg/mL) against a multi-drug-resistant strain (ATCC 700699) and low cytotoxic activity (CC(50)>100 microM) against the human cell line Hep2 (laryngeal carcinoma).
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Compuestos Azo/farmacología , Resistencia a la Meticilina , Quinolonas/farmacología , Staphylococcus aureus/efectos de los fármacos , Compuestos de Sulfhidrilo/química , Antibacterianos/síntesis química , Antibacterianos/toxicidad , Compuestos Azo/síntesis química , Compuestos Azo/química , Compuestos Azo/toxicidad , Línea Celular Tumoral , Ciclización , Flúor/química , Humanos , Estructura Molecular , Quinolonas/síntesis química , Quinolonas/química , Quinolonas/toxicidad , Staphylococcus aureus/fisiología , Relación Estructura-ActividadRESUMEN
This report describes 9H-isothiazolo[5,4-b]quinoline-3,4-diones (ITQs) containing aromatic groups at the 7-position that were prepared using palladium-catalyzed cross-coupling and tested against a panel of susceptible and resistant bacteria. In general, these compounds were more effective against Gram-positive than Gram-negative organisms. Many of the ITQs were more potent than contemporary quinolones and displayed a particularly strong antistaphylococcal activity against a clinically important, multi-drug-resistant strain. In contrast with ITQs reported previously, several of the analogues described in this Letter demonstrated low cytotoxic activity against a human cell line.