2,4-DIAMINOTHIENO [2,3-D]PYRIMIDINE LIPOPHILIC ANTIFOLATES AS INHIBITORS OF PNEUMOCYSTIS-CARINII AND TOXOPLASMA-GONDII DIHYDROFOLATE-REDUCTASE

Ten previously unreported 2,4-diaminothieno[2,3-d]pyrimidine lipophili c dihydrofolate reductase inhibitors were synthesized as potential inh ibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate re ductase. Pivaloylation of 2,4-diamino-5-methylthieno[2,3-d]pyrimidine followed by dibromination with N-bromosuccinimide in the presence of b enzoyl peroxide gave o)-6-bromo-5-(bromomethyl)thieno[2,3-d]pyrimidine , which after condensation with substituted anilines or N-methylanilin es and deprotection with base yielded 2,4-diamino-6-bromo-5-[(substitu ted anilino)methyl]thieno[2,3-d]pyrimidines. Removal of the B-bromo su bstituent was accomplished with sodium borohydride and palladium chlor ide. The reaction yields were generally good to excellent. The product s were tested as inhibitors of dihydrofolate reductase (DHFR) from P. carinii, T. gondii, and rat liver. Although the IC50 could not be reac hed for the 6-unsubstituted compounds because of their extremely poor solubility, three of the five 6-bromo derivatives were soluble enough to allow the IC50 to be determined against all three enzymes. olo)anil ino]methyl]-6-bromothieno[2,3-d]pyrimidine was the most active of the 6-bromo derivatives, with an IC50 of 7.5 mu M against P. carinii DHFR, but showed no selectivity for either P. carinii or T. gondii DHFR rel ative to the enzyme from rat liver.