title: New C25 carbamate rifamycin derivatives are resistant to inactivation by ADP-ribosyl transferases.
abstract: 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.
authors.affiliation: Department of Chemistry, Cumbre Pharmaceuticals Inc., 1502 Viceroy Drive, Dallas, TX 75235, USA. kcombrink@cumbrepharma.com
authors.forename: Keith D
authors.initials: KD
authors.lastname: Combrink
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Denton
authors.forename: Susan
authors.initials: S
authors.lastname: Harran
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Ma
authors.forename: Katrina
authors.initials: K
authors.lastname: Chapo
authors.forename: Dalai
authors.initials: D
authors.lastname: Yan
authors.forename: Eric
authors.initials: E
authors.lastname: Bonventre
authors.forename: Eric D
authors.initials: ED
authors.lastname: Roche
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Doyle
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Robertson
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Lynch
mesh_terms: 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
chemical_list: D000900:Anti-Bacterial Agents; D012294:Rifamycins; D036002:ADP Ribose Transferases; D012293:Rifampin