Extended Aromatic Furan Amidino Derivatives as Anti-Pneumocystis carinii Agents

The syntheses of nine new derivatives of 2,5-bis[4-(N-alkylamidino)phenyl]furans with extended aromatic systems are reported. The interaction of these dicationic furans with poly(dA)*poly(dT) and with the duplex oligomers d(CGCGAATTCGCG)<INF>2</INF> and d(GCGAATTCGC)<INF>2</INF> was determined by T<INF>m</INF> measurement, and the effectiveness of these compounds against the immunosuppressed rat model of Pneumocystis carinii was evaluated. At a screening dose of 10 μmol/kg, 4 of the 12 amidino furans described here are more active than the parent compound <BO>1</BO>. In general, extension of the aromatic system in the absence of a substitution of the amidino nitrogens resulted in higher affinity for DNA than the parent compound as judged by the larger ΔT<INF>m</INF> values and suggests enhanced van der Waals interactions in the amidino furan−DNA complex. Three of the compounds, <BO>3</BO>, <BO>5</BO>, and <BO>11</BO>, yield cysts counts of less than 0<BO>.</BO>1% of control when administered at a dosage of 10 μmol/kg. Compound <BO>3</BO>, which does not have an extended aromatic system, is the most active derivative. Although a direct correlation between anti-P. carinii activity and DNA binding affinity was not observed, all compounds which have significant activity have large ΔT<INF>m</INF> values.