Bis-basic-substituted polycyclic aromatic compounds. A new class of antiviral agents. 7. Bisalkamine esters of 9-oxoxanthene-2,7-dicarboxylic acid, 3,6-bis-basic ethers of xanthen-9-one, and 2,7-bis(aminoacyl)xanthen-9-ones, -xanthenes, and -thioxanthenes
3,6-Bis[2-(dimethylamino)ethoxy]-9H-xanthen-9-one dihydrochloride (4, RMI 10874DA) and 1,1''-(9H-xanthene-2,7-diyl)bis[2-dimethylamino)ethanone] dihydrochloride (16, RMI 11513DA) prolonged survival of mice infected with lethal challenges of encephalomyocarditis (EMC) virus. They were effective by oral and s.c. administration and showed broad-spectrum antiviral activity. They were selected for preclinical evaluation from the 5 series of compounds named in the title that were synthesized in analogy to tilorone and related fluorenone derivatives, described earlier. In addition to 4 and 16, 4 other compounds showed high antiviral activity on oral and s.c. administration. High antiviral activity on s.c. administration was found in bisalkamine esters, bis(aminoacyl)xanthenes, a bis(aminoalkylene)xanthene, bis(aminoacyl)thioxanthenes and the bis-basic ethers of 9-benzylidenexanthenes. Structure-activity relationships showed a decrease of oral activity with increased length of side chains and increased molecular weight of dialkylamino substituents of 3,6-bis-basic ethers of xanthen-9-one and of 2,7-bis(aminoacyl)xanthenes and -xanthen-9-ones. At least 1 carbonyl or alkenyl function in conjugation to the xanthene nucleus either at the 9 position of the nucleus or in the side chains is required for high antiviral activity.