Selective Pneumocystis carinii dihydrofolate reductase inhibitors: Design, synthesis, and biological evaluation of new 2,4-diamino-5- substituted-furo[2,3-d]pyrimidines

Aleem Gangjee, Xin Guo, Sherry F. Queener, Vivian Cody, Nikolai Galitsky, Joe R. Luft, Walter Pangborn

Research output: Contribution to journalArticle

49 Citations (Scopus)

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-dich]oroacetone. 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.

Original languageEnglish (US)
Pages (from-to)1263-1271
Number of pages9
JournalJournal of Medicinal Chemistry
Volume41
Issue number8
DOIs
StatePublished - Apr 9 1998

Fingerprint

Folic Acid Antagonists
Pneumocystis carinii
Pyrimidines
Tetrahydrofolate Dehydrogenase
Naphthols
Liver
Trimethoprim
Rats
Toxoplasma
Hydrophobic and Hydrophilic Interactions
Sulfhydryl Compounds
Amines
X-Rays
Crystal structure
X rays
pyrimidine
2,4-diaminohypoxanthine
2,4-diamino-5-((2-naphthylthio)methyl)furo(2,3-d)pyrimidine
naphthalene
diphenyl

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Selective Pneumocystis carinii dihydrofolate reductase inhibitors : Design, synthesis, and biological evaluation of new 2,4-diamino-5- substituted-furo[2,3-d]pyrimidines. / Gangjee, Aleem; Guo, Xin; Queener, Sherry F.; Cody, Vivian; Galitsky, Nikolai; Luft, Joe R.; Pangborn, Walter.

In: Journal of Medicinal Chemistry, Vol. 41, No. 8, 09.04.1998, p. 1263-1271.

Research output: Contribution to journalArticle

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