Design, synthesis and in vitro evaluation of pyridinium ion based cyclase inhibitors and antifungal agents.
The design, synthesis and in vitro biological evaluation of pyridinium ion based inhibitors of oxidosqualene cyclase enzymes are reported. N-Alkyl- and N-prenylpyridinium ions have been found to be potent and specific inhibitors of Candida albicans oxidosqualene-lanosterol cyclase and to exhibit antifungal activity. The ability of pyridinium ions to inhibit the C. albicans cyclase increases with increasing structural resemblance to a putative monocyclized species formed during the course of the cyclization process. The N-(4E,8E)-5,9,13-trimethyl-4,8,12-tetradecatrien-1- ylpyridinium cation 1 inhibits the C. albicans enzyme at concentrations more than 100-fold lower than does the directly analogous piperidinium derivative 4.
Rose
I C
IC
Department of Chemistry, Stanford University, CA 94305-5080, USA.
Sharpe
B A
BA
Lee
R C
RC
Griffin
J H
JH
Capobianco
J O
JO
Zakula
D
D
Goldman
R C
RC
D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019751:Intramolecular Transferases; D007535:Isomerases / Q000037:antagonists & inhibitors*; D008826:Microbial Sensitivity Tests; D011726:Pyridinium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013261:Sterols / Q000096:biosynthesis; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D004791:Enzyme Inhibitors; C100560:N-(5,9,13-trimethyl-4,8,12-tetradecatrienyl)pyridinium; D011726:Pyridinium Compounds; D013261:Sterols; D007535:Isomerases; D019751:Intramolecular Transferases; C021924:lanosterol synthase