Synthesis and structure-activity studies of novel homomorpholine oxazolidinone antibacterial agents.

A novel series of oxazolidinones were synthesized in which the morpholine C-ring of linezolid was replaced with homomorpholine. In addition to investigating the effect of a homomorpholine C-ring on antibacterial activity, the effect of des-, mono-, di-, and tri-fluoro substitution on the phenyl B-ring was investigated as well. Various C-5 functional groups were also examined, including acetamides and triazoles and carboxamides.

New oxazolidinones.

Due to the emergence of resistance to known antibiotics to various organisms, for example, Staphylococcus, Streptococcus, Enterococci, and Pseudomonas there is a renewed interest in the discovery of new antibacterials. Oxazolidinones, totally synthetic class of novel antibacterials, possess activity against drug-resistant Gram-positive pathogens, especially MRSA. Linezolid, the first approved drug from this class, has shown a great promise in saving lives of many patients by acting against drug-resistant Gram-positive organisms. However, its use is somewhat limited because of its myelotoxicity when used long term (>21 days). Various research groups are active in this area either to improve myelotoxicity profile of linezolid or to expand the spectrum of activity of linezolid. In spite of active research in this area, the discovery of an oxazolidinone possessing improved myelotoxicity compared to linezolid, linezolid-like efficacy, and PK remains challenging.

5,6-Dihydropyran-2-ones possessing various sulfonyl functionalities: potent nonpeptidic inhibitors of HIV protease.

On the basis of previous SAR findings and molecular modeling studies, a series of compounds were synthesized which possessed various sulfonyl moieties substituted at the 4-position of the C-3 phenyl ring substituent of the dihydropyran-2-one ring system. The sulfonyl substituents were added in an attempt to fill the additional S(3)' pocket and thereby produce increasingly potent inhibitors of the target enzyme. Racemic and enantiomerically resolved varieties of selected compounds were synthesized. All analogues in the study displayed decent binding affinity to HIV protease, and several compounds were shown to possess very good antiviral efficacy and safety margins. X-ray crystallographic structures confirmed that the sulfonamide and sulfonate moieties were filling the S(3)' pocket of the enzyme. However, the additional substituent did not provide improved enzymatic inhibitory or antiviral activity as compared to the resolved unsubstituted aniline. The addition of the sulfonyl moiety substitution does not appear to provide favorable pharamacokinectic parameters. Selected inhibitors were tested for antiviral activity in clinical isolates and exhibited similar antiviral activity against all of the HIV-1 strains tested as they did against the wild-type HIV-1. In addition, the inhibitors exhibited good antiviral efficacies against HIV-1 strains that displayed resistance to the currently marketed protease inhibitors.

PD0084430: a non-nucleoside inhibitor of human cytomegalovirus replication in vitro.

Human cytomegalovirus (HCMV) is a major opportunistic pathogen in immunocompromised individuals. Current therapies target viral DNA replication and accumulate mutations that yield cross-resistance among the approved drugs. A novel, non-nucleoside inhibitor of HCMV replication, PD0084430, was identified in a screening assay using the HCMV beta-galactosidase recombinant RC256. The EC(50) for PD0084430 by inhibition of beta-galactosidase production is 1+/-0.7 microM. This antiviral activity was confirmed by yield reduction and plaque reduction assays using HCMV strain AD169. The TC(50) of PD0084430 as measured by (4C)thymidine incorporation is approximately 30 microM and by XTT is approximately 90 microM. The TC(50) for inhibition of cellular proliferation is approximately 20 microM. Time of addition experiments displayed a similar drop in efficacy for both PD0084430 and GCV when added after the onset of viral DNA replication. The transcomplementation assay for viral DNA replication, using a transfected ori(Lyt) containing plasmid, confirmed that viral DNA synthesis was inhibited at the same concentrations that showed antiviral activity. Western blots showed no apparent block of immediate early or early gene expression. Two ganciclovir (GCV) resistant isolates of HCMV tested showed no cross-resistance to PD0084430. These data suggested a potentially promising novel compound that inhibited HCMV at or before viral DNA replication. However, in vivo testing in mice dosed either orally or intraperitoneally showed rapid glucuronidation on the -OH group. SAR studies on this backbone showed that the -OH group was essential for the antiviral activity in vitro.

Synthesis and SAR of novel conformationally restricted oxazolidinones possessing gram-positive and fastidious gram-negative antibacterial activity. Part 2: Amino substitutions on heterocyclic D-ring system.

A novel series of conformationally restricted oxazolidinones was synthesized, in which the heterocyclic D ring was substituted with various amino groups. Several analogs exhibited potent activity against both gram-positive and fastidious gram-negative organisms. Certain amino-substituted analogs also exhibited improved aqueous solubility compared to the corresponding un-substituted heterocyclic D-ring analogs.

A distal methyl substituent attenuates mitochondrial protein synthesis inhibition in oxazolidinone antibacterials.

Oxazolidinone analogs bearing substituted piperidine or azetidine C-rings are described. Analogs with a methyl group at the 3-position of the azetidine ring or the 4-position of the piperidine ring exhibited reduced mitochondrial protein synthesis inhibition while retaining good antibacterial potency.

Synthesis and SAR of novel conformationally-restricted oxazolidinones possessing gram-positive and fastidious gram-negative antibacterial activity. Part 1: Substituted pyrazoles.

A novel series of conformationally-restricted oxazolidinones was synthesized which possess a fused pyrazole ring substituted with various alkyl, aryl and heteroaryl substituents. A number of analogs exhibited potent activity against both gram-positive and fastidious gram-negative organisms.

Conformational constraint in oxazolidinone antibacterials. Part 2: Synthesis and structure-activity studies of oxa-, aza-, and thiabicyclo[3.1.0]hexylphenyl oxazolidinones.

A new class of oxazolidinone antibacterials incorporating oxygen-, nitrogen-, or sulfur-containing heterobicyclic C-rings is described. The in vitro potency and in vivo efficacy of these conformationally constrained oxazolidinone analogs are discussed.

Synthesis and structure-activity studies of novel benzocycloheptanone oxazolidinone antibacterial agents.

We describe a novel class of benzocycloheptanone derived oxazolidinone antibacterial agents. The synthesis and antibacterial activities with structure variation is discussed.

Nonpeptidic HIV protease inhibitors: 6-alkyl-5,6-dihydropyran-2-ones possessing achiral 3-(4-amino/carboxamide-2-t-butyl,5-methylphenyl thio) moiety: antiviral activities and pharmacokinetic properties.

Dihydropyran-2-ones possessing amino and carboxamide functionalities on 3-SPh (2-tert-butyl, 5-methyl) ring were synthesized and evaluated for their antiviral activities. Both the enantiomers of inhibitor 15 were synthesized. The in vitro resistance profile, inhibitory activities against cytochrome P450 isozymes and pharmacokinetic properties of inhibitor 15S will be discussed.

Nonpeptidic HIV protease inhibitors: 6-alkyl-5,6-dihydropyran-2-ones possessing a novel and achiral 3-(2-t-butyl-5-methyl-4-sulfamate)phenylthio moiety.

Dihydropyran-2-ones possessing a sulfamate moiety at the 4-position of the thiophenyl ring were designed to reach S3' pocket of the HIV protease. Synthetic routes for the preparation of thiotosylates possessing 3-(2-t-butyl-5-methyl-4-sulfamate) phenylthio moiety were established. SAR of various sulfamate analogs including HIV protease binding affinities, antiviral activities and therapeutic indices will be described.