CONFORMATIONALLY RESTRICTED ANALOGS OF TRIMETHOPRIM - 2,6-DIAMINO-8-SUBSTITUTED PURINES AS POTENTIAL DIHYDROFOLATE-REDUCTASE INHIBITORS FROM PNEUMOCYSTIS-CARINII AND TOXOPLASMA-GONDII
A. Gangjee et al., CONFORMATIONALLY RESTRICTED ANALOGS OF TRIMETHOPRIM - 2,6-DIAMINO-8-SUBSTITUTED PURINES AS POTENTIAL DIHYDROFOLATE-REDUCTASE INHIBITORS FROM PNEUMOCYSTIS-CARINII AND TOXOPLASMA-GONDII, Journal of medicinal chemistry, 40(19), 1997, pp. 3032-3039
Twenty-two 2,6-diamino-8-substituted purines (2-23) were synthesized,
in which rotation around the two flexible bonds of trimethoprim (TMP),
linking the pyrimidine ring to the side chain phenyl ring, was restri
cted by incorporation into a purine ring, in an attempt to increase th
e potency and selectivity of TMP against dihydrofolate reductase (DHFR
) from the organisms that often cause fatal opportunistic infections i
n patients with AIDS, i.e., Pneumocystis carinii (pc) and Toxcoplasma
gondii (tg). The syntheses of analogues 2-20 were achieved via a one-p
ot reaction of 2,4,5,6-tetraaminopyrimidine and the appropriately subs
tituted benzaldehyde or phenyl acetaldehyde, in acidic methoxyethanol.
Analogues 21-23 were synthesized via nucleophilic displacement of 2,6
-diamino-8-(chloromethyl)purine with the appropriate anilines or 2-nap
hthalenethiol. The compounds were evaluated as inhibitors of pcDHFR an
d tgDHFR with rat liver (rl) DHFR as the mammalian reference enzyme. C
ompound 11, the 3',4'-dichlorophenyl analogue, was as potent as TMP an
d had a selectivity ratio of 13 for pcDHFR, which ranked it as one of
the three most selective inhibitors of pcDHFR (compared to rlDHFR) kno
wn to date. It also displayed a selectivity ratio of 38 for tgDHFR. No
ne of the other analogues showed any improvement compared to TMP in po
tency or selectivity. In the preclinical in vitro screening program of
the National Cancer Institute, compound 11 showed a GI(50) of 10(-6)
M for the inhibition of the growth of 17 tumor cell lines.