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

1999; American Chemical Society; Volume: 42; Issue: 12 Linguagem: Inglês

10.1021/jm990071c

1520-4804

Iris Francesconi, W. David Wilson, Farial A. Tanious, James Edwin Hall, Brendan C. Bender, Richard R. Tidwell, Donald R. McCurdy, David W. Boykin,

HIV/AIDS drug development and treatment

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.