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Discovery of pyrazole-3-carboxylic acid derivatives as dengue virus protease inhibitors with antiviral activity

We present the discovery of pyrazole-3-carboxylic acid derivatives as novel dengue virus (DENV) NS2B-NS3 protease inhibitors. The discovery was triggered by omission of the phenylglycine scaffold of previous lead structures. We established a robust, regioselective synthetic route toward pyrazole-3-c...

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Hauptverfasser: Lang, Johannes (VerfasserIn) , Koch, Jeannette (VerfasserIn) , Dutta, Sudip K. (VerfasserIn) , Leuthold, Mila (VerfasserIn) , Martina, Byron (VerfasserIn) , Klein, Christian D. (VerfasserIn)
Dokumenttyp: Article (Journal) Editorial
Sprache:Englisch
Veröffentlicht: July 15, 2025
In: ACS medicinal chemistry letters
Year: 2025, Jahrgang: 16, Heft: 8, Pages: 1592-1600
ISSN:1948-5875
DOI:10.1021/acsmedchemlett.5c00219
Online-Zugang:Verlag, kostenfrei, Volltext: https://doi.org/10.1021/acsmedchemlett.5c00219
Volltext
Verfasserangaben:Johannes Lang, Jeannette Koch, Sudip K. Dutta, Mila M. Leuthold, Byron Martina, and Christian D. Klein
Beschreibung
Zusammenfassung:We present the discovery of pyrazole-3-carboxylic acid derivatives as novel dengue virus (DENV) NS2B-NS3 protease inhibitors. The discovery was triggered by omission of the phenylglycine scaffold of previous lead structures. We established a robust, regioselective synthetic route toward pyrazole-3-carboxylic acid derivatives. Subsequent SAR studies delivered inhibitors with promising activity against the DENV protease in biochemical and reporter gene assays with EC50 values down to 2.2 μM and antiviral activity against DENV-2 with EC50 values down to 4.1 μM. Active site binding and target specificity were evaluated by a tryptophan fluorescence quenching assay. We further observed negligible cytotoxicity, no inhibition of the off-targets thrombin and trypsin, and promising early stage pharmacokinetic properties. The 2-aminopyrimidine scaffold was identified as a promising nonbasic replacement of the guanidine moiety. In addition, eliminating the highly hydrophobic phenylglycine moiety of previous compound series provides a crucial increase in drug likeness of this novel flaviviral protease inhibitor class.
Beschreibung:Gesehen am 28.11.2025
Beschreibung:Online Resource
ISSN:1948-5875
DOI:10.1021/acsmedchemlett.5c00219

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