Selective Inhibitors of Candida albicans Dihydrofolate Reductase: Activity and Selectivity of 5-(Arylthio)-2,4-diaminoquinazolines

• Published in: Journal of medicinal chemistry Vol. 38; no. 18; pp. 3608 - 3616
• Main Authors: Chan, Joseph H, Hong, Jean S, Kuyper, Lee F, Baccanari, David P, Joyner, Suzanne S, Tansik, Robert L, Boytos, Christine M, Rudolph, Sharon K
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-09-1995
• Subjects: AIDS/HIV; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal agents; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Biological and medical sciences; Candida albicans; Candida albicans - enzymology; Drug Design; Folic Acid Antagonists; Humans; Medical sciences; Mice; Pharmacology. Drug treatments; Pyrimethamine - pharmacology; Pyrimidines - pharmacology; Quinazolines - chemistry; Quinazolines - pharmacology; Recombinant Proteins; Structure-Activity Relationship; Trimethoprim - pharmacology; Trimetrexate - pharmacology; Candida albicans; Nitrogen heterocycle; Quinazoline derivatives; Organic sulfide; Fungi; Antifungal agent; Structure activity relation; Bicyclic compound; Aromatic compound; Fungi Imperfecti; Dihydrofolate reductase; Chemical synthesis; Thallophyta; Enzyme; Rodentia; Oral administration; Enzyme inhibitor; In vitro; In vivo; Vertebrata; Mammalia; Mouse; Animal; Oxidoreductases; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00018a021

The recent increase in fungal infections, especially among AIDS patients, has resulted in the need for more effective antifungal agents. In our search for such agents, we focused on developing compounds which inhibit fungal dihydrofolate reductase (DHFR). A series of 25 5-(arylthio)-2,4-diaminoquinazolines were synthesized as potentially selective inhibitors of Candida albicans DHFR. The majority of the compounds were potent inhibitors of C. albicans DHFR and much less active against human DHFR. High selectivity, as defined by the ratio of the I50 values for human and C. albicans DHFR, was achieved by compounds with bulky and rigid 4-substituents in the phenylthio moiety. For example, 5-[(4-morpholinophenyl)thio]-2,4-diaminoquinazoline displayed a selectivity ratio of 540 and was the most selective inhibitor synthesized to date. Substitution in the 2- or 3-position of the 5-phenylthio group provided only marginal selectivity. 6-Substituted-5-[(4-tert-butylphenyl)thio]-2,4-diaminoquinazolines showed potent activity against the C. albicans enzyme but were equally active against human DHFR. Most of the selective compounds were also good inhibitors of C. albicans cell growth, with minimum inhibitory concentration values as low as 0.05 microgram/ mL.