ABSTRACT
Over 50 phenyl thiazolyl urea and carbamate derivatives were synthesized for evaluation as new inhibitors of bacterial cell-wall biosynthesis. Many of them demonstrated good activity against MurA and MurB and gram-positive bacteria including MRSA, VRE and PRSP. 3,4-Difluorophenyl 5-cyanothiazolylurea (3p) with clog P of 2.64 demonstrated antibacterial activity against both gram-positive and gram-negative bacteria.
Subject(s)
Anti-Bacterial Agents/pharmacology , Carbamates/chemistry , Carbamates/pharmacology , Peptidoglycan/biosynthesis , Phenylthiazolylthiourea/analogs & derivatives , Phenylthiazolylthiourea/pharmacology , Cell Wall/drug effects , Cell Wall/enzymology , Enterococcus faecalis/drug effects , Enterococcus faecalis/enzymology , Escherichia coli/drug effects , Escherichia coli/enzymology , Microbial Sensitivity Tests , Staphylococcus/drug effects , Staphylococcus/enzymologyABSTRACT
Twenty-five 2-phenyl-5,6-dihydro-2H-thieno[3,2-c]pyrazol-3-ol derivatives were synthesized for evaluation as new inhibitors of bacterial cell wall biosynthesis. Many of them demonstrated good inhibitory activity against Staphylococcus aureus MurB, MurC and MurD enzymes in vitro and antimicrobial activity against gram-positive bacteria including MRSA, VRE and PRSP. However, when they were tested in the presence of 4% bovine serum albumin, the MIC values increased to greater than 128 microg/mL against PRSP. None of the compounds demonstrated activity against gram-negative bacteria at MIC <32 microg/mL.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Cell Wall/metabolism , Staphylococcus aureus/metabolism , Anti-Bacterial Agents/pharmacology , Cell Wall/drug effects , Drug Resistance, Bacterial , Genes, Bacterial/genetics , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Staphylococcus aureus/drug effects , Staphylococcus aureus/enzymologyABSTRACT
Sixteen muraymycin derivatives 2-17 were synthesized based on selective reactions of the primary and secondary amino groups of muraymycin C1 (1) with isocyanates and aldehydes. Disubstituted derivatives 3-9 demonstrated no activity against either MraY or MurG at Subject(s)
Anti-Bacterial Agents/chemical synthesis
, Bacterial Proteins/antagonists & inhibitors
, Peptidoglycan/drug effects
, Transferases/antagonists & inhibitors
, Anti-Bacterial Agents/pharmacology
, Cell Wall/enzymology
, Hydrophobic and Hydrophilic Interactions
, Nucleotides
, Peptides
, Peptidoglycan/analogs & derivatives
, Peptidoglycan/biosynthesis
, Peptidoglycan/pharmacology
, Staphylococcus epidermidis/enzymology
, Staphylococcus epidermidis/ultrastructure
, Structure-Activity Relationship
, Transferases (Other Substituted Phosphate Groups)
, Urea
ABSTRACT
A series of pyrazolo[4,3-d]pyrimidine sulfonamides and pyrazolo[3,4-d]pyrimidine sulfonamides have been synthesized. These compounds increase transcription of a calcitonin-luciferase promoter and production of cellular calcitonin in a calcitonin-secretion/RIA assay with minimized phosphodiesterase type 4 inhibitory activity at 30 microM as compared to structurally related xanthine methylene ketones such as denbufyllene. These two series are notable examples of small molecules that act as CT-inducers, a method to potentially treat bone loss diseases.
