Prodrugs of 3-amido bearing pseudomycin analogues: novel antifungal agents.
With the aim of identifying safer pseudomycin derivatives, we synthesized and evaluated a number of N-acyloxymethyl carbamate linked prodrugs of 3-amido pseudomycin analogues. To our satisfaction, all of the prodrug-amide combinations prepared exhibited good in vivo efficacy against murine Candidiasis. When evaluated in a dose elevation study, all of the newly synthesized combinations (e.g., 4A, 6A, 8A, and 8B) demonstrated improved toxicity profiles in comparison to their corresponding 3-amides as well as the parent pseudomycin B.
Sun
X
X
Lilly Research Laboratory, A Division of Eli Lilly and Company, Lilly Corporate Center, IN 46285, Indianapolis, USA.
Zeckner
D
D
Zhang
Y
Y
Sachs
R K
RK
Current
W L
WL
Rodriguez
M
M
Chen
S H
SH
D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D001232:Aspergillus fumigatus / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy*; D002219:Carbamates / Q000737:chemistry; D003453:Cryptococcosis / Q000188:drug therapy*; D003455:Cryptococcus neoformans / Q000187:drug effects; D004195:Disease Models, Animal; D051379:Mice; D008826:Microbial Sensitivity Tests; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity
D000577:Amides; D000935:Antifungal Agents; D002219:Carbamates; D010456:Peptides, Cyclic; D011355:Prodrugs; C425223:pseudomycin B; C036868:methyl carbamate