Bis basic substituted polycyclic aromatic compounds. A new class of antiviral agents. 7. Bisalkamine esters, 3,6 bis basic ethers and 2,7 bis(aminoacyl)xanthen 9 ones

Article abstract of DOI:10.1021/jm00231a012

3,6 Bis[2(dimethylamino)ethoxy] 9H xanthen 9 one dihydrochloride (4, RMI 0874DA) and 1,1' (9H xanthene 2,7 diyl)bis[2 (dimethylamino)ethanone] dihydrochloride (16, RMI 11513DA) were found to prolong survival of mice infected with lethal challenges of encephalomyocarditis (EMC) virus. They were effective by oral as well as subcutaneous administration and showed broad spectrum antiviral activity. They were selected for preclinical evaluation from the five 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, compounds 11, 12, 17, and 18 showed high antiviral activity on oral as well as subcutaneous administration. High antiviral activity on subcutaneous administration was found in the bisalkamine esters 1, 2, and 14, the bis(aminoacyl)xanthenes 23 and 26, the bis(aminoalkylene)xanthene 31, the bis(aminoacyl)thioxanthenes 34-40, and the bis basic ethers of 9 benzylidenexanthenes 41 and 42. 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 one 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.