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