Function-oriented synthesis of simplified caprazamycins: discovery of oxazolidine-containing uridine derivatives as antibacterial agents against drug-resistant bacteria.
The rational simplification of the caprazamycin (CPZ) class of nucleoside natural products was carried out to address their molecular complexity. First, analogues 6-8, where the diazepanone ring of the CPZ was removed and a lipophilic side chain was attached to either the C-7' or N(6') atom, were used to investigate the conformation-activity relationship. On the basis of this relationship, we designed the oxazolidine-containing uridine derivatives 18-21 by restricting the conformation of 6-8. As a result, the (t)Bu ester derivatives 20 were found to be the most active against a range of bacterial strains containing VRE with a potency similar to that of the parent CPZs. This study provides a novel strategy for the development of a new type of antibacterial agent effective against drug-resistant bacteria.
Ii
Kensuke
K
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Ichikawa
Satoshi
S
Al-Dabbagh
Bayan
B
Bouhss
Ahmed
A
Matsuda
Akira
A
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry*; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry; D001381:Azepines / Q000138:chemical synthesis*; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D008055:Lipids / Q000138:chemical synthesis*; D009705:Nucleosides / Q000138:chemical synthesis*; D010080:Oxazoles / Q000737:chemistry; D014529:Uridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D001381:Azepines; D008055:Lipids; D009705:Nucleosides; D010080:Oxazoles; C512217:caprazamycin A; C476914:caprazamycin B; C512218:caprazamycin C; C512219:caprazamycin D; C064210:oxazolidine; D014529:Uridine