ABSTRACT
A non-diaryl quinoline scaffold 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one was identified by screening of diverse set of compounds against M. smegmatis ATP synthase. Herein, we disclose our efforts to develop the structure activity relationship against Mycobacterium tuberculosis (Mtb.H37Rv strain) around the identified hit 1. A scaffold hopping approach was used to identify compounds 14a, 14b and 24a with improved activity against MTb.H37Rv.
Subject(s)
ATP Synthetase Complexes/antagonists & inhibitors , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/enzymology , Quinolines/chemistry , Quinolines/pharmacology , ATP Synthetase Complexes/metabolism , Antitubercular Agents/chemical synthesis , Drug Design , Humans , Mycobacterium tuberculosis/drug effects , Pyrazines/chemical synthesis , Pyrazines/chemistry , Pyrazines/pharmacology , Quinolines/chemical synthesis , Structure-Activity Relationship , Tuberculosis/drug therapy , Tuberculosis/microbiologyABSTRACT
We present here the novel ketolide RBx 14255, a semisynthetic macrolide derivative obtained by the derivatization of clarithromycin, for its in vitro and in vivo activities against sensitive and macrolide-resistant Streptococcus pneumoniae. RBx 14255 showed excellent in vitro activity against macrolide-resistant S. pneumoniae, including an in-house-generated telithromycin-resistant strain (S. pneumoniae 3390 NDDR). RBx 14255 also showed potent protein synthesis inhibition against telithromycin-resistant S. pneumoniae 3390 NDDR. The binding affinity of RBx 14255 toward ribosomes was found to be more than that for other tested drugs. The in vivo efficacy of RBx 14255 was determined in murine pulmonary infection induced by intranasal inoculation of S. pneumoniae ATCC 6303 and systemic infection with S. pneumoniae 3390 NDDR strains. The 50% effective dose (ED50) of RBx 14255 against S. pneumoniae ATCC 6303 in a murine pulmonary infection model was 3.12 mg/kg of body weight. In addition, RBx 14255 resulted in 100% survival of mice with systemic infection caused by macrolide-resistant S. pneumoniae 3390 NDDR at 100 mg/kg four times daily (QID) and at 50 mg/kg QID. RBx 14255 showed favorable pharmacokinetic properties that were comparable to those of telithromycin.
Subject(s)
Anti-Bacterial Agents/pharmacology , Ketolides/pharmacology , Pneumonia, Bacterial/drug therapy , Protein Synthesis Inhibitors/pharmacology , Sepsis/drug therapy , Streptococcus pneumoniae/drug effects , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacokinetics , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Resistance, Bacterial , Ketolides/chemical synthesis , Ketolides/pharmacokinetics , Male , Mice , Microbial Sensitivity Tests , Pneumonia, Bacterial/microbiology , Pneumonia, Bacterial/mortality , Pneumonia, Bacterial/pathology , Protein Synthesis Inhibitors/chemical synthesis , Protein Synthesis Inhibitors/pharmacokinetics , Ribosomes/drug effects , Ribosomes/metabolism , Sepsis/microbiology , Sepsis/mortality , Sepsis/pathology , Streptococcus pneumoniae/pathogenicity , Streptococcus pneumoniae/physiology , Survival AnalysisABSTRACT
A novel series of acylides 4 were designed to overcome antibacterial resistance and evaluated for in vitro and in vivo activity. This series of acylides was designed from clarithromycin by changing the substitution on the desosamine nitrogen, followed by conversion to 3-O-acyl and 11,12-carbamate. These compounds showed significantly potent antibacterial activity against not only Gram-positive pathogens, including macrolide-lincosamide-streptogramin B (MLS(B))-resistant and efflux-resistant strains, but also Gram-negative pathogens such as Haemophilus influenzae. These acylides also showed better activity against telithromycin resistant Streptococcus pneumoniae strains.
