RESUMEN
Substituted 4-quinolone- (1, A = CH) and 1,8-naphthyrid-4-one- (1, A = N) 3-carboxylic acids are currently the only classes of clinically useful antibacterial agents exerting their activity by inhibiting the subunit A of DNA gyrase. Pyrimido[1,6-alpha]benzimidazoles 11 have been found to be a new class of inhibitors of this enzyme. The design, synthesis, and biological activity of these compounds are reported.
Asunto(s)
Bencimidazoles/síntesis química , Pirimidinonas/síntesis química , Inhibidores de Topoisomerasa II , Bencimidazoles/química , Bencimidazoles/farmacología , Inhibidores Enzimáticos/síntesis química , Pirimidinonas/química , Pirimidinonas/farmacología , Relación Estructura-ActividadRESUMEN
A series of bridged monocyclic beta-lactams activated by various groups on the beta-lactam nitrogen (X = OCH2CO2H, OSO3H) has been synthesized and evaluated. Among them, the bridged sulfactams (X = OSO3H) were found to be effective beta-lactamase inhibitors. They inhibit both class A and class C beta-lactamases.
Asunto(s)
Acetatos/síntesis química , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Ácidos Sulfónicos/síntesis química , Inhibidores de beta-Lactamasas , beta-Lactamas/síntesis química , Acetatos/química , Acetatos/farmacología , Ceftriaxona/farmacología , Cefalosporinas/farmacología , Citrobacter freundii/efectos de los fármacos , Citrobacter freundii/enzimología , Sinergismo Farmacológico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Cinética , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/enzimología , Ácidos Sulfónicos/química , Ácidos Sulfónicos/farmacología , beta-Lactamas/química , beta-Lactamas/farmacologíaRESUMEN
A general method for synthesis of 2 beta-alkenyl penam sulfones has been developed. The new compounds inhibited most of the common types of beta-lactamase. The level of activity depended very strongly on the nature of the substituent in the 2 beta-alkenyl group. The inhibited species formed with the beta-lactamase from Citrobacter freundii 1205 was sufficiently stable for X-ray crystallographic studies. These, together with UV absorption spectroscopy and studies of chemical degradation, suggested a novel reaction mechanism for the new inhibitors that might account for their broad spectrum of action. The (Z)-2 beta-acrylonitrile penam sulfone Ro 48-1220 was the most active inhibitor from this class of compound. The inhibitor enhanced the action of, for example, ceftriaxone against a broad selection of organisms producing beta-lactamases. The organisms included strains of Enterobacteriaceae that produce cephalosporinases, which is an exceptional activity for penam sulfones.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Lactamas , Inhibidores de beta-Lactamasas , beta-Lactamas/síntesis química , Ceftriaxona/farmacología , Citrobacter freundii/enzimología , Ácido Clavulánico , Ácidos Clavulánicos/química , Ácidos Clavulánicos/metabolismo , Cristalografía por Rayos X , Sinergismo Farmacológico , Enterobacter/efectos de los fármacos , Enterobacter/enzimología , Inhibidores Enzimáticos/farmacología , Modelos Moleculares , Estructura Molecular , Pseudomonas/efectos de los fármacos , Pseudomonas/enzimología , Espectrofotometría Ultravioleta , beta-Lactamas/química , beta-Lactamas/farmacologíaRESUMEN
Low-molecular-weight beta-sulfonyl- and beta-sulfinylhydroxamic acid derivatives have been synthesized and found to be potent inhibitors of Escherichia coli peptide deformylase (PDF). Most of the compounds synthesized and tested displayed antibacterial activities that cover several pathogens found in respiratory tract infections, including Chlamydia pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. The potential of these compounds as antibacterial agents is discussed with respect to selectivity, intracellular concentrations in bacteria, and potential for resistance development.
Asunto(s)
Amidohidrolasas , Aminopeptidasas/antagonistas & inhibidores , Antibacterianos/síntesis química , Inhibidores Enzimáticos/síntesis química , Ácidos Hidroxámicos/síntesis química , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacología , Chlamydophila pneumoniae/efectos de los fármacos , Cristalografía por Rayos X , Farmacorresistencia Microbiana , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Escherichia coli/metabolismo , Haemophilus influenzae/efectos de los fármacos , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/metabolismo , Ácidos Hidroxámicos/farmacología , Modelos Moleculares , Moraxella catarrhalis/efectos de los fármacos , Mycoplasma pneumoniae/efectos de los fármacos , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/metabolismo , Inhibidores de Proteasas/farmacología , Infecciones del Sistema Respiratorio/microbiología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Bridged monobactams are novel, potent, mechanism-based inhibitors of class C beta-lactamases, designed using X-ray crystal structures of the enzymes. They stabilize the acyl-enzyme intermediate by blocking access of water to the enzyme-inhibitor ester bond. Bridged monobactams are selective class C beta-lactamase inhibitors, with half-inhibition constants as low as 10 nM, and are less effective against class A and class B enzymes (half-inhibition constants > 100 microM) because of the different hydrolysis mechanisms in these classes of beta-lactamases. The stability of the acyl-enzyme complexes formed with class C beta-lactamases (half-lives up to 2 days were observed) enabled determination of their crystal structures. The conformation of the inhibitor moiety was close to that predicted by molecular modeling, confirming a simple reaction mechanism, unlike those of known beta-lactamase inhibitors such as clavulanic acid and penam sulfones, which involve secondary rearrangements. Synergy between the bridged monobactams and beta-lactamase-labile antibiotics could be observed when such combinations were tested against strains of Enterobacteriaceae that produce large amounts of class C beta-lactamases. The minimal inhibitory concentration of the antibiotic of more than 64 mg/L could be decreased to 0.25 mg/L in a 1:4 combination with the inhibitor.