ABSTRACT
Using a furanylthiazole acetic acid as a starting point, a novel series of benzoxazol-5-yl acetic acid derivatives have been identified as heparanase inhibitors. Several compounds possess an IC50 of approximately 200 nM against heparanase, for example, trans 2-[4-[3-(3,4-dichlorophenylamino)-3-oxo-1-propenyl]-2-fluorophenyl]benzoxazol-5-yl acetic acid (16e). Several of the compounds show anti-angiogenic properties. Improvement to the DMPK profile of compounds has provided compounds of potential use in in vivo models.
Subject(s)
Acetates/pharmacology , Benzoxazoles/pharmacology , Enzyme Inhibitors/pharmacology , Glucuronidase/antagonists & inhibitors , Thiazoles/pharmacology , Acetates/chemical synthesis , Acetates/chemistry , Animals , Benzoxazoles/chemical synthesis , Benzoxazoles/chemistry , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Glucuronidase/blood , Kinetics , Mice , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
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
A novel class of 2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acids are described as inhibitors of the endo-beta-glucuronidase heparanase. Several of the compounds, for example, 2-[4-propylamino-5-[5-(4-chloro)phenyl-benzoxazol-2-yl]phenyl]-2,3-dihydro-1,3-dioxo-1H-isoindole-5-carboxylic acid (9c), display potent heparanase inhibitory activity (IC(50) 200-500 nM) and have high selectivity (>100-fold) over human beta-glucuronidase. They also show anti-angiogenic effects. Such compounds should serve as useful biological tools and may provide a basis for the design of novel therapeutic agents.
