Rubrolide analogues as urease inhibitors

Rubrolide analogues as urease inhibitors

Urease is an important virulence factor involved in the colonization and infection of gastric mucosa by Helicobacter pylori . In this work, the urease inhibitory activity of a series of γ -alkylidenebutenolides analogues of natural rubrolides is presented. The compounds were prepared from a commerci...

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Published in:Monatshefte für Chemie Vol. 154; no. 10; pp. 1177 - 1187
Main Authors: Varejão, Jodieh Oliveira Santana, Barbosa, Luiz Cláudio Almeida, Varejão, Eduardo Vinícius Vieira, Coreas, Nidia Magally Galdámez, Morais, Vinicius Stefano Santos, de Oliveira, André Mauricio, Barcelos, Rosimeire Coura, Maltha, Célia Regina Álvares, Modolo, Luzia Valentina
Format: Journal Article
Language:English
Published: Vienna Springer Vienna 01-10-2023
Springer Nature B.V
Subjects:
Analytical Chemistry
Biological activity
Catechol
Chemical bonds
Chemistry
Chemistry and Materials Science
Chemistry/Food Science
Hydrogen bonding
Hydroxyl groups
Inhibitors
Inorganic Chemistry
Organic Chemistry
Original Paper
Physical Chemistry
Theoretical and Computational Chemistry
Carbocycles
Arenes
Butenolides
Alkenes
Lipinski’s rule
Lactones
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Summary:Urease is an important virulence factor involved in the colonization and infection of gastric mucosa by Helicobacter pylori . In this work, the urease inhibitory activity of a series of γ -alkylidenebutenolides analogues of natural rubrolides is presented. The compounds were prepared from a commercial 3,4-dibromofuran-(5 H )-2-one, as previously reported, including three new derivatives. The rubrolide analogues (at 500 µM) showed percentages of urease inhibition ranging from 20.7 to 99.3%. The most active compounds (IC 50 from 111.5 to 306.0 µM) were shown to be more potent than hydroxyurea (IC 50 844.4 µM), a standard urease inhibitor. Rubrolide analogues with phenolic hydroxyl groups revealed higher potency compared with other substances evaluated. Their physicochemical parameters (partition coefficient, molecular weight, hydrogen bonding acceptors, number of hydrogen bonding donor groups, number of rotatable bonds, and the number of aromatic bonds) related to general pharmacokinetic requirements showed drug-like properties for the evaluated rubrolide analogues. Docking studies suggest that the presence of hydroxy groups at the ortho position favors both the formation of reversible interactions with urease and the formation of a covalent adduct with the active site causing blocking of the enzyme, like what happens with catechol, its natural inhibitor. The high biological activity herein reported indicates that rubrolides constitute promising leads for the development of a new class of urease inhibitor drugs. Graphical abstract
ISSN:0026-9247
1434-4475
DOI:10.1007/s00706-023-03106-y