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

• Published in: Journal of medicinal chemistry Vol. 42; no. 12; pp. 2260 - 2265
• Main Authors: Francesconi, Iris, Wilson, W. David, Tanious, Farial A, Hall, James E, Bender, Brendan C, Tidwell, Richard R, McCurdy, Donald, Boykin, David W
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 17.06.1999; Amer Chemical Soc
• Subjects: Amidines - chemical synthesis; Amidines - chemistry; Amidines - pharmacology; Amidines - toxicity; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal agents; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Antifungal Agents - toxicity; Biological and medical sciences; Chemistry, Medicinal; DNA - chemistry; Furans - chemical synthesis; Furans - chemistry; Furans - pharmacology; Furans - toxicity; Immunocompromised Host; Life Sciences & Biomedicine; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pneumonia, Pneumocystis - drug therapy; Rats; Science & Technology; Structure-Activity Relationship; PENTAMIDINE ANALOGS; Pneumonia; Intravenous administration; Rat; Furan derivatives; Pneumocystis carinii; Oxygen heterocycle; Fungi; Antifungal agent; Structure activity relation; Hydrochlorides; Fungi Imperfecti; Chemical synthesis; Thallophyta; Lung disease; Opportunistic infection; Minor groove; Respiratory disease; Rodentia; Vertebrata; Amidine; Chemotherapy; Biological fixation; Experimental disease; Mammalia; Treatment; Animal; DNA; Benzenic compound
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm990071c

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.