ABSTRACT
Synthesis of C(12) des-methyl ketolide is developed featuring an intramolecular epoxide formation/elimination process to establish the C(12) stereocenter. These ketolides are potent against several key respiratory pathogens, including erythromycin resistant erm- and mef-containing strains of Streptococcus pneumoniae.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Carbon/chemistry , Ketolides/chemistry , Ketolides/pharmacology , Anti-Bacterial Agents/chemistry , Gram-Positive Cocci/drug effects , Haemophilus influenzae/drug effects , Ketolides/chemical synthesis , Methylation , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of 2-pyrimidyl-5-amidothiophenes has been synthesized and evaluated for AKT inhibition. SAR studies resulted in potent inhibitors of AKT with IC(50) values as low as single digit nanomolar as represented by compound 2aa. Compound 2aa showed cellular activity including antiproliferation and downstream target modulation. Selectivity profile is described. A co-crystal of 2aa with PKA is determined and discussed.
Subject(s)
Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Thiophenes/chemistry , Thiophenes/chemical synthesis , Cell Line, Tumor , Cell Proliferation , Crystallization , Crystallography, X-Ray , Humans , Inhibitory Concentration 50 , Models, Chemical , Models, Molecular , Protein Binding , Structure-Activity RelationshipABSTRACT
A novel series of C12 vinyl erythromycin derivatives have been discovered which exhibit in vitro and in vivo potency against key respiratory pathogens. The C12 modification involves replacing the natural C12 methyl group in the erythromycin core with a vinyl group via chemical synthesis. From the C12 vinyl macrolide core, a series of C12 vinyl ketolides was prepared. Several compounds were found to be potent against macrolide-sensitive and -resistant bacteria. The C12 vinyl ketolides 6j and 6k showed a similar antimicrobial spectrum and comparable activity to the commercial ketolide telithromycin. However, the pharmacokinetic profiles of C12 vinyl ketolides 6j and 6k in rats differ from that of telithromycin by having higher lung-to-plasma ratios, larger volumes of distribution, and longer half-lives. These pharmacokinetic differences have a pharmacodynamic effect as both 6j and 6k exhibited better in vivo efficacy than telithromycin in rat lung infection models against Streptococcus pneumoniae and Haemophilus influenzae.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Ketolides/chemical synthesis , Vinyl Compounds/chemical synthesis , Animals , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Biological Availability , Drug Resistance, Bacterial , Enterococcus faecalis/drug effects , Haemophilus Infections/drug therapy , Haemophilus influenzae/drug effects , Half-Life , Ketolides/pharmacokinetics , Ketolides/pharmacology , Lung Diseases/drug therapy , Lung Diseases/microbiology , Male , Microbial Sensitivity Tests , Pneumococcal Infections/drug therapy , Rats , Rats, Sprague-Dawley , Staphylococcus aureus/drug effects , Streptococcus pneumoniae/drug effects , Streptococcus pyogenes/drug effects , Structure-Activity Relationship , Vinyl Compounds/pharmacokinetics , Vinyl Compounds/pharmacologyABSTRACT
The hydrophobic component to the binding affinities of one acyclic phosphinate (4) and three macrocyclic phosphonamidate inhibitors (1-3) to the zinc peptidase thermolysin was probed by varying the solvent composition. Increasing the percentage of ethanol in the buffer solution over the range 0-9% increases the inhibition constants, K(i), by up to an order of magnitude. This approach represents an experimental method for distinguishing solvation from conformational or other effects on protein-ligand binding. The size of the "antihydrophobic effect" is correlated with the amount of hydrophobic surface area sequestered from solvent on association of the inhibitor and enzyme, although it is attenuated from that calculated from the surface tension of ethanol-water mixtures. The results are consistent with the Lum-Chandler-Weeks explanation for the size dependence of the hydrophobic effect.
