SELECTIVE PNEUMOCYSTIS-CARINII DIHYDROFOLATE-REDUCTASE INHIBITORS - DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF NEW 2,4-DIAMINO-5-SUBSTITUTED-FURO[2,3-D]PYRIMIDINES

Citation
A. Gangjee 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, 41(8), 1998, pp. 1263-1271
Citations number
21
Categorie Soggetti
Chemistry Medicinal
ISSN journal
00222623
Volume
41
Issue
8
Year of publication
1998
Pages
1263 - 1271
Database
ISI
SICI code
0022-2623(1998)41:8<1263:SPDI-D>2.0.ZU;2-8
Abstract
Nonclassical antifolates, 2,4-diamino-5-substituted-furo[2,3-d]pyrimid ines 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-biphe nyl side chains were synthesized as phenyl ring appended analogues of previously reported 4-diamino-5-(anilinomethyl)furo[2,3-d]pyrimidines. The phenyl ring appended analogues were designed to specifically inte ract with Phe69 of dihydrofolate reductase (DHFR) from Pneumocystis ca rinii (pc) to afford selective inhibitors of pcDHFR. Additional substi tuted 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 s ynthesized. The compounds were prepared by nucleophilic displacement o f 4-diamino-5-(chloromethyl)furo[2,3-d]pyrimidine(2) with the appropri ate thiol, amine, or naphthol. Compound 2 was obtained from 2,4-diamin o-6-hydroxypyrimidine and 1,3-dichloroacetone. The compounds were eval uated as inhibitors against DHFR from P. carinii., Toxoplasma gondii, and rat liver. Two analogues, o-5-[(2'-naphthylthio)methyl]furo[2,3-d] pyrimidine (5) and -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 c arried out, which corroborated the design rationale and indicated a hy drophobic 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.