New C25 carbamate rifamycin derivatives are resistant to inactivation by ADP-ribosyl transferases.
A novel series of 3-morpholino rifamycins in which the C25 acetate group was replaced by a carbamate group were prepared and found to exhibit significantly improved antimicrobial activity than rifampin against Mycobacterium smegmatis. Further characterization of such compounds suggests that relatively large groups attached to the rifamycin core via a C25 carbamate linkage prevent inactivation via ribosylation of the C23 alcohol as catalyzed by the endogenous rifampin ADP-ribosyl transferase of M. smegmatis. SAR studies of the C25 carbamate rifamycin series against M. smegmatis and other bacteria are reported.
Combrink
Keith D
KD
Department of Chemistry, Cumbre Pharmaceuticals Inc., 1502 Viceroy Drive, Dallas, TX 75235, USA. kcombrink@cumbrepharma.com
Denton
Daniel A
DA
Harran
Susan
S
Ma
Zhenkun
Z
Chapo
Katrina
K
Yan
Dalai
D
Bonventre
Eric
E
Roche
Eric D
ED
Doyle
Timothy B
TB
Robertson
Gregory T
GT
Lynch
Anthony S
AS
D036002:ADP Ribose Transferases / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000378:metabolism*; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000235:genetics; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D012293:Rifampin / Q000494:pharmacology; D012294:Rifamycins / Q000138:chemical synthesis* / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D012294:Rifamycins; D036002:ADP Ribose Transferases; D012293:Rifampin