Current drugs for treating human cytomegalovirus (HCMV) infections are limited by resistance and treatment-associated toxicities. In developing mechanistically novel HCMV antivirals, the authors of this article discovered an N -benzyl hydroxypyridone carboxamide antiviral hit ( 8a ) inhibiting HCMV in submicromolar range.
In this article the authors describe the structure–activity relationship (SAR) for 8a , and the characterization of potent analogs for cytotoxicity/cytostatic property, the preliminary mechanism of action, and the absorption, distribution, metabolism and excretion (ADME) properties. The SAR revealed a few pharmacophore features conferring optimal antiviral profile, including the 5-OH, the N-1 benzyl, at least one –CH 2 − in the linker, and a di-halogen substituted phenyl ring in the amide moiety.
The authors identified numerous analogs with sub-micromolar antiviral potency and good selectivity index. The preliminary mechanism of action characterization used a pUL89-C biochemical endonuclease assay, a virus entry assay, a time-of-addition assay, and a compound withdrawal assay. ADME profiling measuring aqueous solubility, plasma and liver microsomal stability, and parallel artificial membrane permeability assay (PAMPA) permeability demonstrated largely favorable drug-like properties. Together, these studies validate the N -benzyl hydroxypyridone carboxamide as a viable chemotype for potent and mechanistically distinct antivirals against HCMV.
Article reference: Senaweera Sameera et al., Discovery of N-benzyl hydroxypyridone carboxamides as a novel and potent antiviral chemotypeagainst human cytomegalovirus (HCMV), Acta Pharmaceutica Sinica B , 2021, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2021.08.019
Keywords: Human cytomegalovirus, N-Benzyl hydroxypyridone carboxamides, Structure–activity relationship, Mechanism of action
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ISSN 2211-3835
Acta Pharmaceutica Sinica B