Inhibition of the HERG Potassium Ion Channel by Different Non-Nucleoside Human Cytomegalovirus Polymerase Antiviral Templates and the Exploration of Variations of a Pyrroloquinoline Series to Reduce Cardiotoxicity Potential

Abstract

Many non-nucleoside human cytomegalovirus (HCMV) inhibitors have been reported in patent and scientific literature, however, none have reached commercialization despite the urgent need for new HCMV treatments. Herein we report select compounds from different templates that all had low micromolar human ether-à-go-go (hERG) ion channel IC50 values. We also describe a series of pyrroloquinoline derivatives that were designed and synthesized to understand the effect of various substitution on human cytomegalovirus (HCMV) polymerase activity, antiviral activity, and hERG inhibition. These results demonstrated that hERG inhibition can be significantly altered based on the substitution on this template. An HCMV inhibitor with low hERG inhibition and reduced cytotoxicity is also described. The results suggest substitution can be fine tuned for the non-nucleoside polymerase inhibitors to reduce hERG inhibition and maintain HCMV antiviral potency.

Note:
Funding declaration: We express our appreciation to D. Lorne Tyrrell and Michael Houghton for funding and supporting this project from the Li Ka Shing Applied Virology Institute (LKSAVI). The LKSAVI is funded by the Government of Alberta through Alberta Innovates.

Conflicts of Interest: None

Keywords: human cytomegalovirus, HCMV, hERG inhibition, non-nucleoside, DNA polymerase inhibitors, pyrroloquinoline