ABSTRACT
Oxazolidinone antibacterial agents, where the N-substituted piperazinyl group of eperezolid was replaced with a N-substituted piperidinyloxy moiety, were synthesized and shown to be active against a variety of resistant and susceptible Gram-positive organisms. The effect of ring size, positional isomerism, and fluorine substitution on antibacterial activity was examined.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Escherichia coli/drug effects , Oxazolidinones/chemical synthesis , Oxazolidinones/pharmacology , Staphylococcus aureus/drug effects , Acetamides/chemistry , Drug Resistance/physiology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Oxazoles/chemistry , Piperidines/chemistryABSTRACT
Amidino benzimidazoles have been identified as inhibitors of the bacterial KinA/Spo0F two-component system (TCS). Many of these inhibitors exhibit good in vitro antibacterial activity against a variety of susceptible and resistant Gram-positive organisms. The moiety at the 2-position of the benzimidazole was extensively modified. In addition, the regioisomeric benzoxazoles, heterocyclic replacements for the benzimidazole, have been synthesized and their activity against the TCS evaluated.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Benzimidazoles/pharmacology , Gram-Positive Bacteria/drug effects , Protein Kinases , Amidines/chemical synthesis , Amidines/pharmacology , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Benzimidazoles/chemical synthesis , Combinatorial Chemistry Techniques , Gram-Positive Bacteria/physiology , Inhibitory Concentration 50 , Microbial Sensitivity Tests , Protein Kinase Inhibitors , Signal Transduction/drug effectsABSTRACT
A new class of inhibitors of the two-component regulatory systems (TCS) of bacteria was discovered based on the salicylanilide screening hits, closantel (1) and tetrachlorosalicylanilide (9). A systematic SAR study versus a model TCS, KinA/Spo0F, demonstrated the importance of electron-attracting substituents in the salicyloyl ring and hydrophobic groups in the anilide moiety for optimal activity. In addition, derivatives 8 and 16, containing the 2, 3-dihydroxybenzanilide structural motif, were potent inhibitors of the autophosphorylation of the KinA kinase, with IC50s of 2.8 and 6. 3 µM, respectively. Compound 8 also inhibited the TCS mediating vancomycin resistance (VanS/VanR) in a genetically engineered Enterococcus faecalis cell line at concentrations subinhibitory for growth. Closantel (1), tetrachlorosalicylanilide (9), and several related derivatives (2, 7, 10, 11, 20) had antibacterial activity against the drug-resistant organisms, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF).
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Bacterial Proteins/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Gram-Positive Bacteria/drug effects , Protein Kinase Inhibitors , Salicylanilides/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacillus subtilis/enzymology , Bacillus subtilis/metabolism , Bacillus subtilis/physiology , Drug Evaluation, Preclinical , Drug Resistance, Microbial , Enterococcus faecium/drug effects , Enterococcus faecium/enzymology , Enterococcus faecium/genetics , Enterococcus faecium/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Gram-Positive Bacteria/enzymology , Gram-Positive Bacteria/physiology , Luciferases/genetics , Luciferases/metabolism , Methicillin Resistance , Microbial Sensitivity Tests , Phosphorylation , Protein Kinases/genetics , Salicylanilides/chemistry , Salicylanilides/pharmacology , Spores, Bacterial/drug effects , Staphylococcus aureus/drug effects , Structure-Activity Relationship , Transcription Factors/antagonists & inhibitors , Transcription Factors/genetics , Vancomycin/pharmacologyABSTRACT
This SAR study has shown that the salicylanilide is the pharmacophore for inhibition of the bacterial two-component system. Hydrophobic substituents improve the potency of inhibitors in this series; however, hydrophobicity is not the sole determinant for inhibition; structural and electronic requirements also exist. Closantel (1) was found to inhibit a two-component system and to have antibacterial activity against drug resistant S. aureus and E. faecium.
