In vitro biological activity and structural analysis of 2,4-diamino-5-(2'-arylpropargyl)pyrimidine inhibitors of Candida albicans.
In order to develop new antifungal agents effective against two species of Candida, we have designed a series of dihydrofolate reductase (DHFR) inhibitors. Here, we explore the structure-activity relationships of these inhibitors toward Candida albicans DHFR by evaluating enzyme inhibition, antifungal activity and toxicity to mammalian cells. Analysis of docked complexes of the enzyme and inhibitors yields the structural basis of relative potency. The meta-biphenyl series of this class exhibits the greatest enzyme inhibition, selectivity and antifungal activity.
Paulsen
Janet L
JL
Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Rd., Storrs, CT 06269, United States.
Liu
Jieying
J
Bolstad
David B
DB
Smith
Adrienne E
AE
Priestley
Nigel D
ND
Wright
Dennis L
DL
Anderson
Amy C
AC
D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D041221:Candida glabrata / Q000187:drug effects / Q000201:enzymology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005493:Folic Acid Antagonists / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D005656:Fungal Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010293:Pargyline / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D011485:Protein Binding; D011487:Protein Conformation; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*
D000935:Antifungal Agents; D005493:Folic Acid Antagonists; D005656:Fungal Proteins; D011743:Pyrimidines; C017205:2,4-diaminopyrimidine; D010293:Pargyline; D013762:Tetrahydrofolate Dehydrogenase