期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 176, 期 -, 页码 187-194出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.05.025
关键词
Flavivirus; Dengue; Protease; Covalent-reversible inhibition; Carbamate; Ester
资金
- Deutsche Forschungsgemeinschaft [KL-1356/3-2]
- EU Marie-Curie grant [748447]
- Marie Curie Actions (MSCA) [748447] Funding Source: Marie Curie Actions (MSCA)
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. (C) 2019 Elsevier Masson SAS. All rights reserved.
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