Discovery of Novel Pyrido[2,3‐b]pyrazine Human Cytomegalovirus Polymerase Inhibitors with Broad Spectrum Antiherpetic Activity and Reduced hERG Inhibition

The development of non‐nucleoside inhibitors targeting human cytomegalovirus (HCMV) polymerase presents a promising approach for enhancing therapeutic treatment for patients with sustained HCMV viremia. A series of non‐nucleoside HCMV DNA polymerase inhibitors with various substitution groups at 2‐postition of the novel pyrido[2,3‐b]pyrazine core was synthesized and investigated. The study focused on optimizing HCMV polymerase inhibition while minimizing off‐target inhibition of human ether‐à‐go‐go (hERG) ion channel. Several compounds exhibited strong antiviral activity against HCMV (typical EC50 <1 µM), with favorable cytotoxicity profiles. A potent lead compound, 27, with an EC50 of 0.33 µM and improved aqueous solubility was identified. Further antiviral assessments revealed the potential of select compounds to target a broad spectrum of herpesviruses, including herpes simplex virus (HSV‐1, HSV‐2) and Epstein‐Barr virus (EBV).