Selective inhibitors of Candida albicans dihydrofolate reductase: activity and selectivity of 5-(arylthio)-2,4-diaminoquinazolines.

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Chan JH, Hong JS, Kuyper LF, Baccanari DP, Joyner SS, Tansik RL, Boytos CM, Rudolph SK

Selective inhibitors of Candida albicans dihydrofolate reductase: activity and selectivity of 5-(arylthio)-2,4-diaminoquinazolines.

J Med Chem. 1995 Sep 1;38(18):3608-16.

PubMed ID
7658448 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
PiritreximDihydrofolate reductaseIC 50 (nM)2N/AN/ADetails
PyrimethamineDihydrofolate reductaseIC 50 (nM)2600N/AN/ADetails
TrimethoprimDihydrofolate reductaseIC 50 (nM)490000N/AN/ADetails