SYNTHESIS AND BIOLOGICAL EVALUATION OF NONCLASSICAL 2,4-DIAMINO-5-METHYLPYRIDO[2,3-D]PYRIMIDINES WITH NOVEL SIDE-CHAIN SUBSTITUENTS AS POTENTIAL INHIBITORS OF DIHYDROFOLATE REDUCTASES
A. Gangjee et al., SYNTHESIS AND BIOLOGICAL EVALUATION OF NONCLASSICAL 2,4-DIAMINO-5-METHYLPYRIDO[2,3-D]PYRIMIDINES WITH NOVEL SIDE-CHAIN SUBSTITUENTS AS POTENTIAL INHIBITORS OF DIHYDROFOLATE REDUCTASES, Journal of medicinal chemistry, 40(4), 1997, pp. 479-485
Nine novel o-5-methyl-6-substituted-pyrido[2,3-d]pyrimidines, 2-10, we
re synthesized as potential inhibitors of Pneumocystis carinii dihydro
folate reductase (pcDHFR) and Toxoplasma gondii dihydrofolate reductas
e (tgDHFR). Compounds 2-5 were designed as conformationally restricted
analogues of trimetrexate (TMQ), in which rotation around tau(3) was
constrained by incorporation of the side chain nitrogen as part of an
indoline or an indole ring. Analogue 6, which has an extra atom betwee
n the side chain nitrogen and the phenyl ring, has its nitrogen as par
t of a tetrahydroisoquinoline ring. Analogues 7-9 are epiroprim (Ro 11
-8958) analogues and contain a pyrrole ring as part of the side chain
substitution on the phenyl ring similar to epiroprim. These analogues
were designed to investigate the role of the pyrrole substitution on t
he phenyl ring of -methyl-6-(anilinomethyl)pyrido[2,3-d]pyrimidines. M
olecular modeling indicated that a pyrrole substituent in the ortho po
sition of the side chain phenyl ring was most likely to interact with
pcDHFR in a manner similar to the pyrrole moiety of epiroprim. Analogu
e 10, in which a phenyl ring replaced a methoxy group, was synthesized
to determine the contribution of a phenyl ring on selectivity, lipoph
ilicity, and cell penetration. The synthesis of analogues 2-4 was achi
eved via reductive amination of 2,4-diamino-5-methyl 6-carboxaldehyde
with the appropriately substituted indolines. The indolines were obtai
ned from the corresponding indoles via NaCNBH3 reductions. Analogues 5
-10 were synthesized by nucleophilic displacement of o-5-methyl-6-(bro
momethyl)-pyrido[2,3-d]pyrimidine with the 5-methoxyindolyl anion, 6,7
-dimethoxytetrahydroisoquinoline, the appropriately substituted pyrrol
oaniline or 2-methoxy-5-phenylaniline. The pyrroloanilines were synthe
sized in two steps by treating the substituted nitroanilines with 2,5-
dimethoxytetrahydrofuran to afford the nitropyrrole intermediates, fol
lowed by reduction of the nitro group with Raney Ni. The analogues wer
e more potent than trimethoprim and epiroprim and more selective than
TMQ and piritrexim against pcDHFR and tgDHFR. Compounds 5 and 10 had I
C50 values of 1 and 0.64 mu M, respectively, for the inhibition of the
growth of T. gondii cells in culture, and showed excellent culture IC
50/enzyme IC50 ratios, which were correlated with their calculated log
P values, indicating a direct relationship between calculated lipophi
licity and cell penetration.