Synthesis and structure-activity relationships of small-molecular di-basic esters, amides and carbamates as flaviviral protease inhibitors

• Verfasst von: Sundermann, Tom R. [VerfasserIn]
• Verfasst von: Dražić, Tonko [VerfasserIn]
• Verfasst von: Klein, Christian D. [VerfasserIn]
• Titel: Synthesis and structure-activity relationships of small-molecular di-basic esters, amides and carbamates as flaviviral protease inhibitors
• Verf.angabe: Tom R. Sundermann, Clarissa V. Benzin, Tonko Dražić, Christian D. Klein
• E-Jahr: 2019
• Jahr: 8 May 2019
• Umfang: 8 S.
• Fussnoten: Gesehen am 16.07.2019
• Titel Quelle: Enthalten in: European journal of medicinal chemistry
• Ort Quelle: Amsterdam [u.a.] : Elsevier Science, 1987
• Jahr Quelle: 2019
• Band/Heft Quelle: 176(2019), Seite 187-194
• ISSN Quelle: 1768-3254
• DOI: doi:10.1016/j.ejmech.2019.05.025
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Carbamate
• Sach-SW: Covalent-reversible inhibition
• Sach-SW: Dengue
• Sach-SW: Ester
• Sach-SW: Flavivirus
• Sach-SW: Protease
• K10plus-PPN: 1669224090

Abstract

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.