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Rubrolide analogues as urease inhibitors

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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 (IC50 from 111.5 to 306.0 µM) were shown to be more potent than hydroxyurea (IC50 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.

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Acknowledgements

We are grateful to Conselho Nacional de Desenvolvimento Científíco e Tecnológico (CNPq) for research fellowships (LCAB and LVM), Fundação de Amparo à Pesquisa de Minas Gerais (FAPEMIG grant # APQ1557-15) for the financial support and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Grant 001) for the research fellowship (JOSV).

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Authors and Affiliations

  1. Department of Chemistry, Universidade Federal de Viçosa, Av. P. H. Rolfs S/N, Viçosa, MG, CEP 36570-900, Brazil

    Jodieh Oliveira Santana Varejão, Luiz Cláudio Almeida Barbosa, Eduardo Vinícius Vieira Varejão, Nidia Magally Galdámez Coreas, Rosimeire Coura Barcelos & Célia Regina Álvares Maltha

  2. Department of Chemistry, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627, Campus Pampulha, Belo Horizonte, MG, CEP 31270-901, Brazil

    Luiz Cláudio Almeida Barbosa & Rosimeire Coura Barcelos

  3. Department of Botany, Universidade Federal de Minas Gerais, Av. Pres. Antônio Carlos, 6627, Campus Pampulha, Belo Horizonte, MG, CEP 31270-901, Brazil

    Vinicius Stefano Santos Morais & Luzia Valentina Modolo

  4. Department of Environment, Centro Federal de Educação Tecnológica de Minas Gerais, Alameda das Perdizes, 61, Campus Contagem, Contagem, MG, CEP 32146-054, Brazil

    André Mauricio de Oliveira

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  1. Jodieh Oliveira Santana Varejão
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  2. Luiz Cláudio Almeida Barbosa
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Correspondence to Jodieh Oliveira Santana Varejão.

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Varejão, J.O.S., Barbosa, L.C.A., Varejão, E.V.V. et al. Rubrolide analogues as urease inhibitors. Monatsh Chem 154, 1177–1187 (2023). https://doi.org/10.1007/s00706-023-03106-y

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