Conformationally restricted tricyclic analogues of lipophilic pyrido[2,3-d]pyrimidine antifolates

The effect of conformational restriction of the C9-N10 bridge on inhibitory potency and selectivity of trimetrexate against dihydrofolate reductase, w as studied. Specifically three nonclassical tricyclic 1,3-diamino-8-(3',4', 5'-trimethoxybenzyl)-7,9-dihydro-pyrrolo[3,4-c]pyrido[2,3-d]pyrimidin-6(5H, 8H)-one (4), 1,3-diamino-8-(3',4',5'-trimethoxybenzyl (5) and 1,3-diamino-( 8H)-(3',4',5'-trimethoxybenzyl)-7,9-dihydro-pyrrolo[3,4-c]pyrido[2,3-d]pyri midine (7) antifolates were synthesized. The tricyclic analogues 4 and 5 we re obtained via the regiospecific cyclocondensation of the beta -keto ester 17 with 2,4,6-triaminopyrimidine. The analogue 7 was obtained via reductio n of the lactam 4 with borane in tetrahydrofuran. Compounds 4, 5 and 7 were evaluated as inhibitors of dihydrofolate reductase from Pneumocystis carin ii, Toxoplasma gondii and rat liver. All three compounds were more selectiv e than trimetrexate against Pneumocystis carinii dihydrofolate reductase an d significantly more selective than trimetrexate against Toxoplasma gondii dihydrofolate reductase compared with rat liver dihydrofolate reductase.