2,5-Bis[4-(N-alkylamidino)phenyl]furans as Anti-Pneumocystis carinii Agents

Abstract

The syntheses of 12 new 2,5-bis[4-(N-alkylamidino)phenyl]furans are reported. The interaction of these dicationic furans with poly(dA-dT) and with the duplex oligomer d(CGCGAATTCGCG)₂ was determined by T_m measurements, and the effectiveness of these compounds against the immunosuppressed rat model of Pneumocystis carinii was evaluated. At the screening dose of 10 μmol/kg, 9 of the 14 N-alkylamidino furans described here are more active than the parent compound 1. Substitution of an alkyl group on the amidino nitrogen, except for in 9, 13, and 15, resulted in higher affinity for DNA than the parent compound as judged by the larger ΔT_m values and suggests enhanced van der Waals interactions in the bis-amidine−DNA complex. Five of the compounds, 3, 5, 7, 10, and 12, yield cyst counts of less than 0.1% of control when administered at a dosage of 10 μmol/kg. Five compounds, 1, 6, 8, 10, and 12, show significant activity at a dosage of approximately 1 μmol/kg; 12 is the most active derivative, and it is approximately 100 times more effective than pentamidine in this animal model.