Synthesis and structure-activity relationships of small-molecular di-basic esters, amides and carbamates as flaviviral protease inhibitors
Inhibitors of the flaviviral serine proteases, which are crucial for the replication of dengue and West-Nile virus, have attracted much attention over the last years. A dibasic 4-guanidinobenzoate was previously reported as inhibitor of the dengue protease with potency in the low-micromolar range. I...
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| Hauptverfasser: | , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
8 May 2019
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| In: |
European journal of medicinal chemistry
Year: 2019, Jahrgang: 176, Pages: 187-194 |
| ISSN: | 1768-3254 |
| DOI: | 10.1016/j.ejmech.2019.05.025 |
| Online-Zugang: | Verlag, Volltext: http://dx.doi.org/10.1016/j.ejmech.2019.05.025
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| Verfasserangaben: | Tom R. Sundermann, Clarissa V. Benzin, Tonko Dražić, Christian D. Klein |
| Zusammenfassung: | Inhibitors of the flaviviral serine proteases, which are crucial for the replication of dengue and West-Nile virus, have attracted much attention over the last years. A dibasic 4-guanidinobenzoate was previously reported as inhibitor of the dengue protease with potency in the low-micromolar range. In the present study, this lead structure was modified with the intent to explore structure-activity relationships and obtain compounds with increased drug-likeness. Substitutions of the guanidine moieties, the aromatic rings, and the ester with other functionalities were evaluated. All changes were accompanied by a loss of inhibition, indicating that the 4-guanidinobenzoate scaffold is an essential element of this compound class. Further experiments indicate that the target recognition of the compounds involves the reversible formation of a covalent adduct. |
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| Beschreibung: | Gesehen am 16.07.2019 |
| Beschreibung: | Online Resource |
| ISSN: | 1768-3254 |
| DOI: | 10.1016/j.ejmech.2019.05.025 |