DICATIONIC DIARYLFURANS AS ANTIPNEUMOCYSTIS CARINII AGENTS

Seven dicationic 2,5-diarylfurans have been synthesized, and their int eractions with poly(dA-dT) and the duplex oligomer d(CGCCAATTCGCG)(2) were evaluated by T-m measurements. The inhibition of topoisomerase II isolated from Giardia lamblia, the inhibition of growth of G. lamblia in cell culture by; these furans, and the effectiveness of these comp ounds against Pneumocystis carinii in the immunosuppressed rat model h ave been assessed. Strong binding affinities to poly(dA-dT) and to the oligomer were observed for the dicationic furans, and the interaction strength is directly correlated to the biological activity of the com pounds. An X-ray structure for the complex of the dicationic amidine d erivative, 2,5-bis(4-guanylphlenyl)furan (1), with the oligomer demons trates the snug fit of these compounds with the AATT minor-groove bind ing site and hydrogen bonds to AT base pairs at the floor of the minor groove. The stronger DNA binding molecules are the most effective inh ibitors of topoisomerase II and G. lamblia in cell culture, and there is a correlation for both DNA interaction and topoisomerase II inhibit ion with the biological activity of these componds against G. lamblia. Compound 1 is the most effective against P. carinii, it is more activ e and less toxic than pentamidine on intravenous administration and it is also effective by oral dosage. The results presented here suggest a model for the biological action of these compounds in which the dica tion first binds in the minor groove of DNA and forms a complex that r esults in the inhibition of the microbial topoisomerase II enzyme.