1. New linezolid-like 1,2,4-oxadiazoles active against Gram-positive multiresistant pathogens
- Author
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Carmela Bonaccorso, Laura Rizzi, Paola Pierro, Cosimo G. Fortuna, Gianluigi Caltabiano, Giuseppe Musumarra, Clementina Cocuzza, Laura Goracci, Rosario Musumeci, Alessandra Bulbarelli, Annalisa Guarcello, Antonio Palumbo Piccionello, Andrea Pace, Fortuna, C, Bonaccorso, C, Bulbarelli, A, Caltabiano, G, Rizzi, L, Goracci, L, Musumarra, G, Pace, A, Palumbo Piccionello, A, Guarcello, A, Pierro, P, Cocuzza, C, Musumeci, R, Fortuna, CG, and Cocuzza, CEA
- Subjects
Methicillin-Resistant Staphylococcus aureus ,Models, Molecular ,Cell viability ,Staphylococcus aureus ,Molecular model ,Cell Survival ,Microbial Sensitivity Tests ,Antimicrobial activity ,Crystallography, X-Ray ,medicine.disease_cause ,Drug design ,Microbiology ,Structure-Activity Relationship ,chemistry.chemical_compound ,oxadiazoles, linezolid, antibiotics ,Cell Line, Tumor ,Drug Resistance, Multiple, Bacterial ,Morpholine ,Acetamides ,Drug Discovery ,medicine ,Humans ,Moiety ,Structure–activity relationship ,Oxazolidinones ,Pharmacology ,Oxadiazoles ,Linezolid ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Organic Chemistry ,Settore CHIM/06 - Chimica Organica ,Hep G2 Cells ,General Medicine ,biochemical phenomena, metabolism, and nutrition ,bacterial infections and mycoses ,Settore CHIM/08 - Chimica Farmaceutica ,Methicillin-resistant Staphylococcus aureus ,Combinatorial chemistry ,Oxazolidinone ,Anti-Bacterial Agents ,MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA ,Antibacterial activity ,Software - Abstract
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.
- Published
- 2013