ABSTRACT
The first inhibitors of fungal protein: mannosyl transferase 1 (PMT1) are described. They are based upon rhodanine-3-acetic acid and several compounds have been identified, for example, 5-[[3-(1-phenylethoxy)-4-(2-phenylethoxy)phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid (5a), which inhibit Candida albicans PMT1 with IC(50)s in the range 0.2-0.5 microM. Members of the series are effective in inducing changes in morphology of C. albicans in vitro that have previously been associated with loss of the transferase activity. These compounds could serve as useful tools for studying the effects of protein O-mannosylation and its relevance in the search for novel antifungal agents.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Mannosyltransferases/antagonists & inhibitors , Rhodanine/analogs & derivatives , Rhodanine/pharmacology , Candida albicans/drug effects , Candida albicans/enzymology , Enzyme Inhibitors/pharmacology , Fungi/drug effects , Fungi/enzymology , Microbial Sensitivity Tests , Rhodanine/chemical synthesis , Structure-Activity RelationshipABSTRACT
The synthesis of racemic cytisine has been completed using (i)N-selective alkylation of 6-bromopyridone with bromide and (ii) Pd(0) mediated intramolecular alpha-arylation of lactam as key steps to achieve rapid assembly of the tricyclic core skeleton of the lupin alkaloids.
