Coumarin inhibitors of gyrase B with N-propargyloxy-carbamate as an effective pyrrole bioisostere.
The synthesis and biological profile in vitro of a series of coumarin inhibitors of gyrase B bearing a N-propargyloxycarbamate at C-3' of noviose is presented. Replacement of the 5-methylpyrrole-2-carboxylate of coumarin drugs with an N-propargyloxycarbamate bioisostere leads to analogues with improved antibacterial activity. Analysis of crystal structures of coumarin antibiotics with the 24 kDa N-terminal domain of the gyrase B protein provides a rational for the excellent inhibitory potency of C-3' N-alkoxycarbamates.
Periers
A M
AM
Medicinal Chemistry, Hoechst Marion Roussel, Romainville, France.
Laurin
P
P
Ferroud
D
D
Haesslein
J L
JL
Klich
M
M
Dupuis-Hamelin
C
C
Mauvais
P
P
Lassaigne
P
P
Bonnefoy
A
A
Musicki
B
B
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002219:Carbamates / Q000138:chemical synthesis* / Q000494:pharmacology; D003374:Coumarins / Q000138:chemical synthesis* / Q000494:pharmacology; D027081:DNA Gyrase; D004278:DNA, Superhelical / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D011758:Pyrroles / Q000737:chemistry*; D013211:Staphylococcus aureus / Q000187:drug effects; D013237:Stereoisomerism; D059005:Topoisomerase II Inhibitors
D000900:Anti-Bacterial Agents; D002219:Carbamates; D003374:Coumarins; D004278:DNA, Superhelical; D004791:Enzyme Inhibitors; D011758:Pyrroles; D059005:Topoisomerase II Inhibitors; D027081:DNA Gyrase