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

Citation
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
Citations number
26
Categorie Soggetti
Chemistry Medicinal
ISSN journal
00222623
Volume
40
Issue
4
Year of publication
1997
Pages
479 - 485
Database
ISI
SICI code
0022-2623(1997)40:4<479:SABEON>2.0.ZU;2-K
Abstract
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.