title: Design, synthesis and in vitro evaluation of pyridinium ion based cyclase inhibitors and antifungal agents.
abstract: 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.
authors.affiliation: Department of Chemistry, Stanford University, CA 94305-5080, USA.
authors.forename: I C
authors.initials: IC
authors.lastname: Rose
authors.forename: B A
authors.initials: BA
authors.lastname: Sharpe
authors.forename: R C
authors.initials: RC
authors.lastname: Lee
authors.forename: J H
authors.initials: JH
authors.lastname: Griffin
authors.forename: J O
authors.initials: JO
authors.lastname: Capobianco
authors.forename: D
authors.initials: D
authors.lastname: Zakula
authors.forename: R C
authors.initials: RC
authors.lastname: Goldman
mesh_terms: 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
chemical_list: 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