title: Selective inhibitors of Candida albicans dihydrofolate reductase: activity and selectivity of 5-(arylthio)-2,4-diaminoquinazolines.
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.
authors.affiliation: Division of Organic Chemistry, Burroughs Wellcome Company, Research Triangle Park, North Carolina 27709, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Chan
authors.forename: J S
authors.initials: JS
authors.lastname: Hong
authors.forename: L F
authors.initials: LF
authors.lastname: Kuyper
authors.forename: D P
authors.initials: DP
authors.lastname: Baccanari
authors.forename: S S
authors.initials: SS
authors.lastname: Joyner
authors.forename: R L
authors.initials: RL
authors.lastname: Tansik
authors.forename: C M
authors.initials: CM
authors.lastname: Boytos
authors.forename: S K
authors.initials: SK
authors.lastname: Rudolph
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D002176:Candida albicans / Q000201:enzymology*; D015195:Drug Design; D005493:Folic Acid Antagonists; D006801:Humans; D051379:Mice; D011739:Pyrimethamine / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins; D013329:Structure-Activity Relationship; D014295:Trimethoprim / Q000494:pharmacology; D016597:Trimetrexate / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D005493:Folic Acid Antagonists; D011743:Pyrimidines; D011799:Quinazolines; D011994:Recombinant Proteins; C013474:2,4-diaminoquinazoline; D014295:Trimethoprim; C024530:piritrexim; D016597:Trimetrexate; D011739:Pyrimethamine