Anti-Pneumocystis carinii pneumonia activity of dicationic diaryl methylpyrimidines

Article abstract of DOI:10.1016/S0223-5234(97)89640-7

Synthesis of 2,4-bis-(4-amidinophenyl)-6-methylpyrimidine 5, 2,4-bis-[(4-imidazolin-2-yl)phenyl]-6-methylpyrimidine 6, 2,4-bis[(4-N-i-propylamidino)phenyl]-6-methylpyrimidine 7, and 2,4-bis[(4-N-isopentylamidino)phenyl]-6-methylpyrimidine 8 starting from 4-bromobenzamidine and 4'-bromoacetophenone is reported. The synthesis of 2,4-bis-(4-amidinophenyl)-5-methylpyrimidine 12 and 2,4-bis-[(4-imidazolin-2-yl)phenyl]-5-methylpyrimidine 13, also beginning with 4-bromobenzamidine and 4'-bromopropiophenone is described. A synthesis of 4,6-bis-(4-amidinophenyl)-2-methylpyrimidine 17, 4,6-bis-[(4-imidazolin-2-yl)phenyl]-2-methylpyrimidine 18, 4,6-bis[(4-N-i-propylamidino)phenyl]-2-methylpyrimidine 19 and 4,6-bis[(4-N-n-propylamidino)phenyl]-2-methylpyrimidine 20 starting from acetamidine and 1,3-bis(4-bromophenyl)propenone is reported. Compounds 5-7 and 17-20 all bind strongly to the minor groove of poly-dA·dT whereas 8, 12 and 13 bind less tightly as judged by their ΔT(m) values. A similar trend was noted for binding of these compounds to the 12-mer-d(CGCGAATTCGCG)₂. Compounds 5, 7, and 17 are more active and less toxic than pentamidine at its effective dose when evaluated against Pneumocystis carinii pneumonia (PCP) in the immunosuppressed rat model.