2,4-DIAMINO-6,7-DIHYDRO-5H-CYCLOPENTA[D]PYRIMIDINE ANALOGS OF TRIMETHOPRIM AS INHIBITORS OF PNEUMOCYSTIS-CARINII AND TOXOPLASMA-GONDII DIHYDROFOLATE-REDUCTASE

Three previously unreported ino-5-[(3,4,5-trimethoxyphenyl)alkyl]-6,7- dihydro- 5H-cyclopenta[d]pyrimidines 15a-c were synthesized as analogu es of trimethoprim (TMP) and were tested as inhibitors of Pneumocystis carinii, Toxoplasma gondii, and rat liver dihydrofolate reductase (DH FR). The length of the alkyl bridge between the cyclopenta[d]pyrimidin e and trimethoxyphenyl moiety ranged from one in 15a to three carbons in 15c. The products were tested as competitive inhibitors of the redu ction of dihydrofolate by Pneumocystis carinii, Toxoplasma gondii, and rat liver DHFR. Compounds 15a-c had IC50 values of >32, 1.8 and 1.3 m u M, respectively, against P. carinii DHFR, as compared to 12 mu M for TMP. Against the T. gondii enzyme, 15a-c had IC50 values of 21, 0.14 and 0.14 mu M, respectively as compared to 2.7 mu M for TMP. Inhibitor s 15b and 15c with two-and three-carbon bridges were significantly mor e potent than 15a against all three enzymes. Unlike TMP, 15b and 15c w ere better inhibitors of the rat liver enzyme than of the microbial en zymes. The potency of 15b and 15c against rat liver DHFR was less than has been reported for the corresponding 6,7-dihydro-5H-cyclopenta[d]p yrimidines with a classical p-aminobenzoyl-L-glutamate side chain as i nhibitors of bovine, murine, and human DHFR.