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

Abstract

Dicationic 2,4-bis(4-amidinophenyl)furans 5−10 and 2,4-bis(4-amidinophenyl)-3,5-dimethylfurans 14 and 15 have been synthesized. Thermal melting studies revealed high binding affinity of the compounds to poly(dA-dT) and to the duplex oligomer d(CGCGAATTCGCG)₂. 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 5, 7−10 at the dose of 10 μmol/kg/d; however, the isopropyl analogue 7 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.