ABSTRACT
Mycobacterium tuberculosis infection is responsible for a global pandemic. New drugs are needed that do not show cross-resistance with the existing front-line therapeutics. A triazine antitubercular hit led to the design of a related pyrimidine family. The synthesis of a focused series of these analogs facilitated exploration of their in vitro activity, in vitro cytotoxicity, and physiochemical and absorption-distribution-metabolism-excretion properties. Select pyrimidines were then evaluated for their pharmacokinetic profiles in mice. The findings suggest a rationale for the further evolution of this promising series of antitubercular small molecules, which appear to share some similarities with the clinical compound PA-824 in terms of activation, while highlighting more general guidelines for the optimization of small-molecule antitubercular agents.
Subject(s)
Antitubercular Agents/chemical synthesis , Drug Design , Mycobacterium tuberculosis/drug effects , Nitroimidazoles/chemistry , Pyrimidines/chemical synthesis , Tuberculosis/drug therapy , Animals , Antitubercular Agents/blood , Antitubercular Agents/pharmacokinetics , Antitubercular Agents/pharmacology , Disease Models, Animal , Drug Stability , Female , Humans , Mice , Microbial Sensitivity Tests , Mycobacterium tuberculosis/growth & development , Nitroimidazoles/blood , Nitroimidazoles/pharmacokinetics , Nitroimidazoles/pharmacology , Pyrimidines/blood , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Solubility , Structure-Activity Relationship , Tuberculosis/blood , Tuberculosis/microbiologyABSTRACT
Novel antibacterial fluoroquinolone agents bearing a 4-alkylidenylpiperidine 7-position substituent are active against quinolone-susceptible and quinolone-resistant gram-positive bacteria, including Streptococcus pneumoniae and MRSA. Analogs 22b, 23c, and 24 demonstrated superior in vitro and in vivo efficacy to ciprofloxacin against these cocci.
Subject(s)
Anti-Bacterial Agents/pharmacology , Gram-Positive Bacteria/drug effects , Quinolones/pharmacology , Topoisomerase Inhibitors/pharmacology , HumansABSTRACT
A series of pyrrolopyridine-substituted oxazolidinones containing various C-5 acetamide isosteres was synthesized and the structure-antibacterial activity relationships determined against a representative panel of susceptible and resistant Gram-positive bacteria.
Subject(s)
Acetamides/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Oxazolidinones/chemistry , Oxazolidinones/pharmacology , Pyridines/chemistry , Anti-Bacterial Agents/chemistry , Enterococcus/drug effects , Linezolid , Molecular Structure , Oxazolidinones/chemical synthesis , Staphylococcus aureus/drug effects , Structure-Activity RelationshipABSTRACT
A novel series of oxazolidinones containing a pyrroloaryl substituent was synthesized and screened against a representative panel of susceptible and resistant Gram-positive bacteria. Several members of this series were found to have antibacterial activity comparable to or better than linezolid.
