EXTENDED AROMATIC FURAN AMIDINO DERIVATIVES AS ANTIPNEUMOCYSTIS CARINII AGENTS

The. syntheses of nine new derivatives of 2,5-bis[4-(N-alkylamidino)ph enyl]furans with extended aromatic systems are reported. The interacti on of these dicationic furans with poly(dA)poly(dT) and with the dupl ex oligomers d(CGCGAATTCGCG)(2) and d(GCGAATTCGC)(2) was determined by T-m measurement, and the effectiveness of these compounds against the immunosuppressed rat model of Pneumocystis carinii was evaluated. At a screening dose of 10 mu mol/kg, 4 of the 12 amidino furans described here are more active than the parent compound 1. In general, extensio n of the aromatic system in the absence of a substitution of the amidi no nitrogens resulted in higher affinity for DNA than the parent compo und as judged by the larger Delta T-m values and suggests enhanced van der Waals interactions in the amidino furan-DNA complex. Three of the compounds, 3, 5, and 11, yield cysts counts of less than 0.1% of cont rol when administered at a dosage of 10 mu mol/kg. Compound 3, which d oes not have an extended aromatic system, is the most active derivativ e. Although a direct correlation between anti-P. carinii activity and DNA binding affinity was not observed, all compounds which have signif icant activity have large Delta T-m values.