engleski

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)(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, 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 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 control when administered at a dosage of 10 mu mol/kg. Compound 3, 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 Delta T-m values

substituted bis-benzimidazoles; DNA-binding affinity; minor-groove; antigiardial activity; giardia-lamblia; inhibition; pentamidine; dications; analogs; berenil

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