2,4-Diphenyl Furan Diamidines as Novel Anti-Pneumocystis carinii Pneumonia Agents

Dicationic 2,4-bis(4-amidinophenyl)furans <BO>5</BO>−<BO>10</BO> and 2,4-bis(4-amidinophenyl)-3,5-dimethylfurans <BO>14</BO> and <BO>15</BO> have been synthesized. Thermal melting studies revealed high binding affinity of the compounds to poly(dA-dT) and to the duplex oligomer d(CGCGAATTCGCG)<INF>2</INF>. All of the new compounds were effective against Pneumocystis carinii pneumonia in the immunosuppressed rat model with up to 200-fold increase in activity compared to the control compound pentamidine. No toxicity was noted for <BO>5</BO>, <BO>7</BO>−<BO>10</BO> at the dose of 10 μmol/kg/d; however, the isopropyl analogue <BO>7</BO> showed toxicity comparable to pentamidine at the dosage of 20 μmol/kg/d. Dimethylation of the parent compound on the furan ring resulted in reduced activity and increased toxicity.