Synthesis and evaluation of acridine- and acridone-based anti-herpes agents with topoisomerase activity.
The discovery of new non-nucleoside antiviral compounds is of significant and growing interest for treating herpes virus infections due to the emergence of nucleoside-resistant strains. Using a whole cell virus-induced cytopathogenic assay, we tested a series of substituted triaryl heterocyclic compounds including acridones, xanthones, and acridines. The compounds which showed activity against Herpes Simplex-1 and/or Herpes Simplex-2 were further assayed for inhibition of topoisomerase activity to gain insight into the mechanism of action. The results indicate that the acridine analogs bearing substituted carboxamides and bulky 9-amino functionalities are able to inhibit herpes infections as well as inhibit topoisomerase II relaxation of supercoiled DNA. Given the mechanism of action of amsacrine (a closely related, well-studied 9-amino substituted acridine), the compounds were further tested in a DNA topoisomerase II cleavage assay to determine if the compounds function as poisons. The results show that the acridines synthesized in this study function through a different mechanism to that of amsacrine, most likely by blocking topoisomerase binding to DNA (akin to that of aclarubicin). This not only suggests a unique mechanism of action in treating herpes virus infections, but also may be of great interest in the development of anticancer agents that target topoisomerase II activity.
Goodell
John R
JR
Department of Medicinal Chemistry and Center for Drug Design, University of Minnesota, Minneapolis, 55455, USA.
Madhok
Avni A
AA
Hiasa
Hiroshi
H
Ferguson
David M
DM
D000166:Acridines / Q000138:chemical synthesis / Q000494:pharmacology*; D054831:Acridones; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D026942:DNA Topoisomerases / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000201:enzymology; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D059005:Topoisomerase II Inhibitors; D059003:Topoisomerase Inhibitors; D014779:Virus Replication / Q000187:drug effects*
D000166:Acridines; D054831:Acridones; D000998:Antiviral Agents; D059005:Topoisomerase II Inhibitors; D059003:Topoisomerase Inhibitors; C041300:acridone; D026942:DNA Topoisomerases; D004250:DNA Topoisomerases, Type II