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

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)<INF>2</INF> was determined by T<INF>m</INF> 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 <BO>1</BO>. Substitution of an alkyl group on the amidino nitrogen, except for in <BO>9</BO>, <BO>13</BO>, and <BO>15</BO>, 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 bis-amidine−DNA complex. Five of the compounds, <BO>3</BO>, <BO>5</BO>, <BO>7</BO>, <BO>10</BO>, and <BO>12</BO>, yield cyst counts of less than 0.1% of control when administered at a dosage of 10 μmol/kg. Five compounds, <BO>1</BO>, <BO>6</BO>, <BO>8</BO>, <BO>10</BO>, and <BO>12</BO>, show significant activity at a dosage of approximately 1 μmol/kg; <BO>12</BO> is the most active derivative, and it is approximately 100 times more effective than pentamidine in this animal model.