The synthesis and antibacterial activity of oxazolidinones containing dihydro-1,2-oxazine and 2-pyrazoline ring systems are described. Linezolid analogs utilizing dihydro-1,2-oxazines as morpholine mimics were prepared utilizing a nitrosoamine/diene 4+2 cycloaddition strategy. Pyrazolidine, hexahydro-pyridazine, and 2-pyrazoline analogs more closely related to eperezolid were also prepared.
View Article and Find Full Text PDFNocathiacin I (1) was converted to its deoxy indole analogue, nocathiacin II (2), another natural product, by a unique and facile chemical process. This process was applied to nocathiacin IV (4), generating the lactone analogue of glycothiohexide alpha (5), which was also prepared from nocathiacin II by a mild hydrolytic process. In contrast to glycothiohexide alpha (3), this lactone analogue (5) was found to exhibit in vivo antibacterial efficacy in an animal (mouse) infection model.
View Article and Find Full Text PDFThe synthesis and antibacterial activity of a series of nocathiacin I derivatives (4-20) containing polar water solubilizing groups is described. Thiol-Michael adducts containing acidic polar groups have reduced antibacterial activity whereas those with basic polar groups have retained very good antibacterial activity.
View Article and Find Full Text PDFSeveral nocathiacin I analogues (4-35) were synthesized and evaluated for their antibacterial activity. Most of these semi-synthetic analogues retained very good in vitro and in vivo antibacterial activity of 1.
View Article and Find Full Text PDFAntimicrob Agents Chemother
July 2004
BMS-433771 is a potent inhibitor of respiratory syncytial virus (RSV) replication in vitro. Mechanism of action studies have demonstrated that BMS-433771 halts virus entry through inhibition of F protein-mediated membrane fusion. BMS-433771 also exhibited in vivo efficacy following oral administration in a mouse model of RSV infection (C.
View Article and Find Full Text PDFThe synthesis and antibacterial activity of a series of new nocathiacin I derivatives (1-12) containing polar water solubilizing groups is described. Most of these compounds exhibited potent antibacterial activity and have improved water solubility. In addition, compounds 5, 7-9 also exhibited potent in vivo activity.
View Article and Find Full Text PDFAntimicrob Agents Chemother
February 2004
BMS-433771 was found to be a potent inhibitor of respiratory syncytial virus (RSV) replication in vitro. It exhibited excellent potency against multiple laboratory and clinical isolates of both group A and B viruses, with an average 50% effective concentration of 20 nM. Mechanism-of-action studies demonstrated that BMS-433771 inhibits the fusion of lipid membranes during both the early virus entry stage and late-stage syncytium formation.
View Article and Find Full Text PDFSeveral semi-synthetic bis- and mono-O-alkyl nocathiacin derivatives were synthesized and evaluated for antibacterial activity. Mono-O-alkyl N-hydroxyindole analogues 3a-l were prepared by regioselective alkylation. Bis-O-alkyl nocathiacins 4a-f were obtained by treatment with base and excess electrophile.
View Article and Find Full Text PDFSynthesis of phosphonooxymethyl derivatives of ravuconazole, 2 (BMS-379224) and 3 (BMS-315801) and their biological evaluation as potential water-soluble prodrugs of ravuconazole are described. The phosphonooxymethyl ether analogue 2 (BMS-379224) and N-phosphonooxymethyl triazolium salt 3 (BMS-315801) were both prepared from ravuconazole (1) and bis-tert-butyl chloromethylphosphate, but under two different conditions. Both derivatives were highly soluble in water and converted to the parent in alkaline phosphatase, and also in vivo (rat).
View Article and Find Full Text PDFThiazolyl peptide antibiotics, nocathiacin I, II and III, were identified in a culture of Nocardia sp. WW-12651 (ATCC 202099). They exhibit potent in vitro activity (ng/ml) against a wide spectrum of gram-positive bacteria, including multiple-drug resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), multi-drug resistant Enterococcus faecium (MREF) and fully penicillin-resistant Streptococcus pneumoniae (PRSP), and demonstrate excellent in vivo efficacy in a systemic Staphylococcus aureus infection mice model.
View Article and Find Full Text PDFBMS-247243, a novel cephalosporin inhibitory for methicillin-resistant staphylococci, primarily has activity against gram-positive bacteria. The activities of BMS-247243, cefotaxime, and ceftriaxone against streptococci and Streptococcus pneumoniae were similar. BMS-247243 inhibits Enterococcus faecalis but not Enterococcus faecium.
View Article and Find Full Text PDFThe recent emergence of methicillin-resistant Staphylococcus aureus (MRSA) with decreased susceptibility to vancomycin has intensified the search for alternative therapies for the treatment of infections caused by this organism. One approach has been to identify a beta-lactam with improved affinity for PBP 2a, the target enzyme responsible for methicillin resistance in staphylococci. BMS-247243 is such a candidate, with MICs that inhibit 90% of isolates tested (MIC(90)s) of 4, 2, and 8 microg/ml for methicillin-resistant strains of S.
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