Muraymycins, novel peptidoglycan biosynthesis inhibitors: semisynthesis and SAR of their derivatives.
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 <or=100 microg/mL whereas mono substituted derivatives 11-17 demonstrated good inhibitory activity, well correlated with the lipophilicity of the substituent introduced. In particular, the activity of derivatives 13 and 14 was comparable to that of muraymycin C1 in this assay.
Lin
Yang-I
YI
Chemical Sciences and Infectious Diseases, Wyeth Research, Pearl River, NY 10965, USA. linf@wyeth.com
Li
Zhong
Z
Francisco
Gerardo D
GD
McDonald
Leonard A
LA
Davis
Rachel A
RA
Singh
Guy
G
Yang
Youjun
Y
Mansour
Tarek S
TS
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D002473:Cell Wall / Q000201:enzymology; D057927:Hydrophobic and Hydrophilic Interactions; D009711:Nucleotides; D010455:Peptides; D010457:Peptidoglycan / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000187:drug effects* / Q000494:pharmacology; D013212:Staphylococcus epidermidis / Q000201:enzymology / Q000648:ultrastructure; D013329:Structure-Activity Relationship; D014166:Transferases / Q000037:antagonists & inhibitors*; D017855:Transferases (Other Substituted Phosphate Groups); D014508:Urea
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D009711:Nucleotides; D010455:Peptides; D010457:Peptidoglycan; C475706:muraymycin A1; C475707:muraymycin A3; C475708:muraymycin C1; D014508:Urea; D014166:Transferases; D017855:Transferases (Other Substituted Phosphate Groups); C079803:mraY protein, Bacteria