Novel semi-synthetic nocathiacin antibiotics: synthesis and antibacterial activity of bis- and mono-O-alkylated derivatives.
Several semi-synthetic bis- and mono-O-alkyl nocathiacin derivatives were synthesized and evaluated for antibacterial activity. Mono-O-alkyl N-hydroxyindole analogues 3a-l were prepared by regioselective alkylation. Bis-O-alkyl nocathiacins 4a-f were obtained by treatment with base and excess electrophile. A one-pot protection-alkylation-deprotection strategy was developed for the preparation of mono-O-alkyl hydroxypyridine analogues 5a,b. Most of the bis- and mono-O-alkyl nocathiacins maintained good in vitro activity but showed reduced in vivo efficacy when compared with the natural product. The excellent in vivo activity and improved water solubility of phosphate analogues 3m and 4g suggest their use as potential pro-drugs.
Regueiro-Ren
Alicia
A
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. alicia.regueiroren@bms.com
Naidu
B Narasimhulu
BN
Zheng
Xiaofan
X
Hudyma
Thomas W
TW
Connolly
Timothy P
TP
Matiskella
John D
JD
Zhang
Yunhui
Y
Kim
Oak K
OK
Sorenson
Margaret E
ME
Pucci
Michael
M
Clark
Junius
J
Bronson
Joanne J
JJ
Ueda
Yasutsugu
Y
D000478:Alkylation / Q000187:drug effects; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D013293:Enterococcus faecalis / Q000187:drug effects / Q000254:growth & development; D036341:Intercellular Signaling Peptides and Proteins; D008826:Microbial Sensitivity Tests / Q000706:statistics & numerical data; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000254:growth & development
D000900:Anti-Bacterial Agents; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C463319:nocathiacin I