RESUMEN
This study describes the antibacterial properties of synthetically produced mixed aryl-alkyl disulfide compounds as a means to control the growth of Staphylococcus aureus and Bacillus anthracis. Some of these compounds exerted strong in vitro bioactivity. Our results indicate that among the 12 different aryl substituents examined, nitrophenyl derivatives provide the strongest antibiotic activities. This may be the result of electronic activation of the arylthio moiety as a leaving group for nucleophilic attack on the disulfide bond. Small alkyl residues on the other sulfur provide the best activity as well, which for different bacteria appears to be somewhat dependent on the nature of the alkyl moiety. The mechanism of action of these lipophilic disulfides is likely similar to that of previously reported N-thiolated beta-lactams, which have been shown to produce alkyl-CoA disulfides through a thiol-disulfide exchange within the cytoplasm, ultimately inhibiting type II fatty acid synthesis. However, the mixed alkyl-CoA disulfides themselves show no antibacterial activity, presumably due to the inability of the highly polar compounds to cross the bacterial cell membrane. These structurally simple disulfides have been found to inhibit beta-ketoacyl-acyl carrier protein synthase III, or FabH, a key enzyme in type II fatty acid biosynthesis, and thus may serve as new leads to the development of effective antibacterials for MRSA and anthrax infections.
Asunto(s)
Bacillus anthracis/citología , Bacillus anthracis/efectos de los fármacos , Disulfuros/química , Disulfuros/farmacología , Resistencia a la Meticilina/efectos de los fármacos , Staphylococcus aureus/citología , Staphylococcus aureus/efectos de los fármacos , Alquilación , Disulfuros/síntesis química , Metilación , Viabilidad Microbiana/efectos de los fármacos , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The synthetic correlation between two different antibiotic frameworks, the beta-lactams and 2-oxazolidinones, is described for the first time. In this approach, 2-oxazolidinones are prepared in stereomerically pure form from 3-hydroxy beta-lactams by a ring-opening-cyclization isomerization process. Application of this methodology to the total synthesis of the cytokine modulator, (-)-cytoxazone, and its three stereoisomers is demonstrated. [reaction: see text].
Asunto(s)
Antibacterianos/síntesis química , Oxazoles/síntesis química , beta-Lactamas/química , Antibacterianos/química , Ciclización , Oxazoles/química , Estereoisomerismo , Streptomyces/metabolismoRESUMEN
This study focuses on the mechanism of action of N-alkylthio beta-lactams, a new family of antibacterial compounds that show promising activity against Staphylococcus and Bacillus microbes. Previous investigations have determined that these compounds are highly selective towards these bacteria, and possess completely unprecedented structure-activity profiles for a beta-lactam antibiotic. Unlike penicillin, which inhibits cell wall crosslinking proteins and affords a broad spectrum of bacteriocidal activity, these N-thiolated lactams are bacteriostatic in their behavior and act through a different mechanistic mode. Our current findings indicate that the compounds react rapidly within the bacterial cell with coenzyme A (CoA) through in vivo transfer of the N-thio group to produce an alkyl-CoA mixed disulfide species, which then interferes with fatty acid biosynthesis. Our studies on coenzyme A disulfide reductase show that the CoA thiol-redox buffer is not perturbed by these compounds; however, the lactams appear to act as prodrugs. The experimental evidence that these beta-lactams inhibit fatty acid biosynthesis in bacteria, and the elucidation of coenzyme A as a primary cellular target, offers opportunities for the discovery of other small organic compounds that can be developed as therapeutics for MRSA and anthrax infections.
Asunto(s)
Antibacterianos/farmacología , Staphylococcus aureus/efectos de los fármacos , Compuestos de Sulfhidrilo/química , Ácidos Tiosulfónicos/farmacología , beta-Lactamas/farmacología , Coenzima A/antagonistas & inhibidores , Coenzima A/metabolismo , Disulfuros/farmacología , Pruebas de Sensibilidad Microbiana , Oxidación-Reducción , Relación Estructura-ActividadRESUMEN
In this report, we describe a new family of N-thiolated 2-oxazolidinones having antibacterial activity against methicillin-resistant Staphylococcus aureus and Bacillus anthracis. The effect of ring substituents and stereochemistry on antibacterial activity of these oxazolidinones closely parallels that previously reported for N-thiolated beta-lactam antibiotics.
Asunto(s)
Antibacterianos/farmacología , Bacillus anthracis/efectos de los fármacos , Resistencia a la Meticilina , Oxazolidinonas/farmacología , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/síntesis química , Farmacorresistencia Microbiana , Pruebas de Sensibilidad Microbiana , Oxazolidinonas/síntesis química , Compuestos de Sulfhidrilo/química , beta-Lactamas/farmacologíaRESUMEN
The melanocortin receptors have been implicated as potential targets for a number of important therapeutic indications, including inflammation, sexual dysfunction, and obesity. We identified compound 1, an arylpiperazine attached to the dipeptide H-d-Tic-d-p-Cl-Phe-OH, as a novel melanocortin subtype-4 receptor (MC4R) agonist through iterative directed screening of nonpeptidyl G-protein-coupled receptor biased libraries. Structure-activity relationship (SAR) studies demonstrated that substitutions at the ortho position of the aryl ring improved binding and functional potency. For example, the o-isopropyl-substituted compound 29 (K(i) = 720 nM) possessed 9-fold better binding affinity compared to the unsubstituted aryl ring (K(i) = 6600 nM). Sulfonamide 39 (K(i) = 220 nM) fills this space with a polar substituent, resulting in a further 2-fold improvement in binding affinity. The most potent compounds such as the diethylamine 44 (K(i) = 60 nM) contain a basic group at this position. Basic heterocycles such as the imidazole 50 (K(i) = 110 nM) were similarly effective. We also demonstrated good oral bioavailability for sulfonamide 39.