Mixture-based heterocyclic combinatorial positional scanning libraries: discovery of bicyclic guanidines having potent antifungal activities against Candida albicans and Cryptococcus neoformans.
A mixture-based synthetic combinatorial library of more than 100,000 bicyclic guanidines was generated in a positional scanning format and assayed for activity against Candida albicans. Potent individual bicyclic guanidines were directly identified following the screening of the library. Time-kill curve studies indicated bactericidal activities for the individual bicyclic guanidines. These compounds also showed potent activity against Cryptococcus neoformans. These studies demonstrate the value of using mixture-based combinatorial positional scanning libraries made up of heterocyclic compounds for the rapid identification of novel classes of antifungal compounds.
Blondelle
S E
SE
Torrey Pines Institute for Molecular Studies, San Diego, California 92121, USA. blondell@tpims.org
Crooks
E
E
Ostresh
J M
JM
Houghten
R A
RA
D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects*; D003455:Cryptococcus neoformans / Q000187:drug effects*; D015195:Drug Design; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D001643:Bridged Bicyclo Compounds; D006146:Guanidines