biostudies-literatureBai BLi Ka Shing Applied Virology Institutee202400629https://www.ebi.ac.uk/biostudies/studies/S-EPMC11911297biostudies-literatureUnknown20(6)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 assessmentChemMedChemDiscovery of Novel Pyrido[2,3-b]Pyrazine Human Cytomegalovirus Polymerase Inhibitors with Broad Spectrum Antiherpetic Activity and Reduced hERG Inhibition.PMC11911297RES0055738Srinivas Kandadai AHena MBai BShen JNieman JABelovodskiy AHoughton MfalseDiscovery 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 assessment2025-01-01T00:00:00Z2025 Mar2025-04-26T08:44:20.261Z2025-04-06T12:48:04.629ZS-EPMC119112973965677810.1002/cmdc.202400629