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Article
Selective Pneumocystis carinii dihydrofolate reductase inhibitors: design, synthesis and biological evaluation of new 2,4-diamino-5-substituted-furo[2,3-d]pyrimidines
Journal of Medicinal Chemistry
  • Aleem Gangjee, Duquesne University
  • Xin Guo, Duquesne University
  • Sherry F. Queener, Indiana University
  • Vivian Cody, Hauptman-Woodward Medical Research Institute, Inc.
  • Nikolai Galitsky, Hauptman-Woodward Medical Research Institute, Inc.
  • Joe R. Luft, Hauptman-Woodward Medical Research Institute, Inc.
  • Walter Pangborn, Hauptman-Woodward Medical Research Institute, Inc.
Document Type
Article
DOI
10.1021/jm970537w
Publication Date
3-18-1998
Abstract
Nonclassical antifolates, 2,4-diamino-5-substituted-furo[2, 3-d]pyrimidines 3-12 with bridge region variations of C8-S9, C8-N9, and C8-O9 and 1-naphthyl, 2-naphthyl, 2-phenoxyphenyl, 4-phenoxyphenyl, and 2-biphenyl side chains were synthesized as phenyl ring appended analogues of previously reported 2, 4-diamino-5-(anilinomethyl)furo[2,3-d]pyrimidines. The phenyl ring appended analogues were designed to specifically interact with Phe69 of dihydrofolate reductase (DHFR) from Pneumocystis carinii (pc) to afford selective inhibitors of pcDHFR. Additional substituted phenyl side chains which include 2,5-dichloro, 3,4-dichloro, 3,4,5-trichloro, 3-methoxy, and 2,5-dimethoxy analogues 13-17 were also synthesized. The compounds were prepared by nucleophilic displacement of 2,4-diamino-5-(chloromethyl)furo[2,3-d]pyrimidine(2) with the appropriate thiol, amine, or naphthol. Compound 2 was obtained from 2,4-diamino-6-hydroxypyrimidine and 1, 3-dichloroacetone. The compounds were evaluated as inhibitors against DHFR from P. carinii, Toxoplasma gondii, and rat liver. Two analogues, 2,4-diamino-5-[(2'-naphthylthio)methyl]furo[2, 3-d]pyrimidine (5) and 2,4-diamino-5-[(2'-phenylanilino)methyl]furo[2,3-d]pyrimidine (11) showed significant selectivity and potency for pcDHFR compared to trimethoprim. The X-ray crystal structure of 5 with pcDHFR was also carried out, which corroborated the design rationale and indicated a hydrophobic interaction of the naphthalene ring of 5 and Phe69 of pcDHFR which is responsible, in part, for the more than 18-fold selectivity of 5 for pcDHFR as compared with rat liver DHFR.
Citation Information
Aleem Gangjee, Xin Guo, Sherry F. Queener, Vivian Cody, et al.. "Selective Pneumocystis carinii dihydrofolate reductase inhibitors: design, synthesis and biological evaluation of new 2,4-diamino-5-substituted-furo[2,3-d]pyrimidines" Journal of Medicinal Chemistry Vol. 41 Iss. 8 (1998) p. 1263 - 1271 ISSN: 0022-2623
Available at: http://works.bepress.com/xin-guo/34/