ANTIPNEUMOCYSTIS CARINII PNEUMONIA ACTIVITY OF DICATIONIC DIARYL METHYLPYRIMIDINES

Synthesis of 2,4-bis-(4-amidinophenyl)-6-methylpyrimidine 5, bis-[(4-i midazolin-2-yl)phenyl]-6-methylpyrimidine 6, is[(4-N-i-propylamidino)p henyl]-6-methylpyrimidine 7, and s[(4-N-isopentylamidino)phenyl]-6-met hylpyrimidine starting from 4-bromobenzamidine and 4'-bromoacetophenon e is reported. The synthesis of 2,4-bis-(4-amidinophenyl)-5-methylpyri midine 12 and bis-[(4-imidazolin-2-yl)phenyl]-5-methylpyrimidine 13, a lso beginning with 4-bromobenzamidine and 4'-bromopropiophenone is des cribed. A synthesis of 4,6-bis-(4-amidinophenyl)-2-methylpyrimidine 17 , bis-[(4-imidazolin-2-yl)phenyl]-2-methylpyrimidine 18, is[(4-N-i-pro pylamidino)phenyl]-2-methylpyrimidine 19 and is[(4-N-n-propylamidino)p henyl]-2-methylpyrimidine 20 starting from acetamidine and 1,3-bis(4-b romophenyl)propenone is reported. Compounds 5-7 and 17-20 all bind str ongly to the minor groove of poly-dA.dT whereas 8, 12 and 13 bind less tightly as judged by their Delta T-m values. A similar trend was note d for binding of these compounds to the 12-mer-d(CGCGAATTCGCG)(2). Com pounds 5, 7, and 17 are more active and less toxic than pentamidine at its effective dose when evaluated against Pneumocystis carinii pneumo nia (PCP) in the immunosuppressed rat model.