Vol.:(0123456789) 1 3 Monatshefte für Chemie - Chemical Monthly (2023) 154:1177–1187 https://doi.org/10.1007/s00706-023-03106-y ORIGINAL PAPER Rubrolide analogues as urease inhibitors Jodieh Oliveira Santana Varejão 1  · Luiz Cláudio Almeida Barbosa 1,2  · Eduardo Vinícius Vieira Varejão 1  · Nidia Magally Galdámez Coreas 1  · Vinicius Stefano Santos Morais 3  · André Mauricio de Oliveira 4  · Rosimeire Coura Barcelos 1,2  · Célia Regina Álvares Maltha 1  · Luzia Valentina Modolo 3 Received: 22 February 2023 / Accepted: 10 July 2023 / Published online: 22 July 2023 © Springer-Verlag GmbH Austria, part of Springer Nature 2023 Abstract 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-(5H)-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 accep- tors, 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 O O Br R1 R2 R3 R4 Rubrolide analogs Keywords Alkenes · Arenes · Butenolides · Carbocycles · Lactones · Lipinski’s rule * Jodieh Oliveira Santana Varejão jodieh.varejao@ufv.br Luiz Cláudio Almeida Barbosa lcab@ufmg.br Luzia Valentina Modolo lvmodolo@icb.ufmg.br 1 Department of Chemistry, Universidade Federal de Viçosa, Av. P. H. Rolfs S/N, Viçosa, MG CEP 36570-900, Brazil 2 Department of Chemistry, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627, Campus Pampulha, Belo Horizonte, MG CEP 31270-901, Brazil 3 Department of Botany, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627, Campus Pampulha, Belo Horizonte, MG CEP 31270-901, Brazil 4 Department of Environment, Centro Federal de Educação Tecnológica de Minas Gerais, Alameda das Perdizes, 61, Campus Contagem, Contagem, MG CEP 32146-054, Brazil