RESUMEN
The effects of side chain modification and chirality in linezolid-like 1,2,4-oxadiazoles have been studied to design new potent antibacterials against Gram-positive multidrug-resistant pathogens. The adopted strategy involved a molecular modelling approach, the synthesis and biological evaluation of new designed compounds, enantiomers separation and absolute configuration assignment. Experimental determination of the antibacterial activity of the designed (S)-1-((3-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-oxazolidin-2-one-5-yl)methyl)-3-methylthiourea and (S)-1-((3-(3-fluoro-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-oxazolidin-2-one-5-yl)methyl)-3-methylthiourea against multidrug resistant linezolid bacterial strains was higher than that of linezolid.
Asunto(s)
Acetamidas/química , Antibacterianos/química , Oxadiazoles/química , Oxazolidinonas/química , Acetamidas/farmacología , Antibacterianos/síntesis química , Antibacterianos/farmacología , Sitios de Unión , Supervivencia Celular/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Bacterias Grampositivas/genética , Células Hep G2 , Humanos , Linezolid , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Simulación del Acoplamiento Molecular , Conformación de Ácido Nucleico , Oxadiazoles/síntesis química , Oxadiazoles/farmacología , Oxazolidinonas/farmacología , ARN Ribosómico 23S/química , ARN Ribosómico 23S/genética , Staphylococcus aureus/efectos de los fármacos , EstereoisomerismoRESUMEN
The design, synthesis, and antibacterial activity of 4-alkyliden-azetidin-2-ones as new antimicrobial agents against multidrug-resistant pathogens is reported. 4-Alkyliden-azetidin-2-ones were easily obtained using an original protocol starting from 4-acetoxy-azetidinones and diazoesters. Parent compounds were further elaborated to obtain a small library of 4-alkylidene derivatives. A molecular modeling approach using GRID descriptors based on the concept of VRS identified attractive drug candidates and contributed to the rationalization of functional group effects in QSARs. The in vitro antibacterial activity of the new agents was evaluated against 43 recent clinical isolates of antibiotic-susceptible and -resistant Gram-positive and Gram-negative pathogens by determining their minimum inhibitory concentrations (MICs). The most active compound showed MIC values ranging from 0.25 to 32 mg/L against some of the bacterial species tested. Interestingly, some compounds demonstrated similar activity against methicillin-susceptible and -resistant strains of Staphylococcus aureus suggesting possible alternative mechanisms of action of these agents, supported by citotoxicity and preliminary scanning electron microscopy studies.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Diseño de Fármacos , Farmacorresistencia Bacteriana , Bacterias Gramnegativas/efectos de los fármacos , beta-Lactamas/química , beta-Lactamas/farmacología , Alquilación , Antibacterianos/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Enterococcus/efectos de los fármacos , Bacterias Gramnegativas/fisiología , Humanos , Estructura Molecular , Staphylococcus/efectos de los fármacos , Relación Estructura-Actividad , beta-Lactamas/síntesis químicaRESUMEN
A series of N-methylthio-ß-lactams with antibacterial activity were thoroughly evaluated as antioxidants. We found that only the presence of a polyphenolic moiety anchored to the ß-lactam ring ensured an adequate antioxidant potency. New compounds, efficiently combining in one structure antioxidant and antibacterial activity, may provide a promising basis for the development of new leads useful in adverse clinical conditions such as in cystic fibrosis patients, in whom colonization by MRSA and epithelial damage by chronic pulmonary oxidative stress take place.
Asunto(s)
Antibacterianos/farmacología , Antioxidantes/farmacología , Azetidinas/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Monobactamas/farmacología , Sulfuros/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antioxidantes/síntesis química , Antioxidantes/química , Azetidinas/síntesis química , Azetidinas/química , Fibrosis Quística/microbiología , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Monobactamas/síntesis química , Monobactamas/química , Relación Estructura-Actividad , Sulfuros/síntesis química , Sulfuros/químicaRESUMEN
The synthesis and the in vitro antibacterial activity of novel linezolid-like oxadiazoles are reported. Replacement of the linezolid morpholine C-ring with 1,2,4-oxadiazole results in an antibacterial activity against Staphylococcus aureus both methicillin-susceptible and methicillin-resistant comparable or even superior to that of linezolid. While acetamidomethyl or thioacetoamidomethyl moieties in the C(5) side-chain are required, fluorination of the phenyl B ring exhibits a slight effect on an antibacterial activity but its presence seems to reduce the compounds cytotoxicity. Molecular modeling performed using two different approaches - FLAP and Amber software - shows that in the binding pose of the newly synthesized compounds as compared with the crystallographic pose of linezolid, the 1,2,4-oxadiazole moiety seems to perfectly mimic the function of the morpholinic ring, since the H-bond interaction with U2585 is retained.
Asunto(s)
Acetamidas/química , Antibacterianos/farmacología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Oxadiazoles/farmacología , Oxazolidinonas/química , Antibacterianos/síntesis química , Antibacterianos/química , Línea Celular Tumoral , Supervivencia Celular , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Linezolid , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Programas Informáticos , Relación Estructura-ActividadRESUMEN
The increasing emergence of multidrug-resistant microorganisms is one of the greatest challenges in the clinical management of infectious disease. New antimicrobial agents are therefore urgently required, particularly in the treatment of chronic and recurrent infections often associated with antibiotic-resistant pathogens, as in the case of cystic fibrosis (CF) patients. This study reports the antibacterial activity of a series of monocyclic ß-lactams with an alkylidenecarboxyl chain or electron-withdrawing groups such as 4-OAc, 4-SAc, and 4-SO(2)Ph at the C4 position of the ring. N-Unsubstituted and N-thiomethyl derivatives were compared. A total of 33 azetidinones were tested for their activity against Gram-positive and Gram-negative bacterial clinical isolates. The combination of an N-thiomethyl group and a benzyl ester on the 4-alkylidene side chain were found to increase the potency against Gram-positive bacteria. The N-thiomethyl group clearly elevated the activity of 4-acetoxyazetidinones relative to the corresponding NH derivatives. The most active compounds showed minimum inhibitory concentration (MIC) values of 4 and 8 mg L(-1) against methicillin-resistant Staphylococcus aureus isolated from pediatric patients with CF.