Ácidos cinamoilidroxâmicos como inibidores de urease: síntese, avaliação da atividade inibitória e estudos sobre o mecanismo de inibição

• Ano de defesa: 2024
• Autor(a) principal: Luciana Pereira Silva Viana
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Minas Gerais; Brasil; ICX - DEPARTAMENTO DE QUÍMICA; Programa de Pós-Graduação em Química; UFMG
• Palavras-chave em Português: Ácidos hidroxâmicos alfa,beta-insaturados; Inibidor de urease; Mecanismo de interação; Helicobacter pylori; Aceptor de Michael; ³,³-unsaturated hydroxamic acids; Urease inhibitor; Interaction mechanism; Michael acceptor; Química orgânica; Ácidos hidroxâmicos; Urease – Inibidores; Agentes antiinfecciosos; Proteus (Bactéria); Cinética de enzimas; Biofísica; Esterificação (Química); Ácidos carboxílicos
• Link de acesso: http://hdl.handle.net/1843/68084; https://orcid.org/0000-0002-1132-4508

Hydroxamic acids (HAs) constitute a class of compounds recognized for their chelating properties and ability to inhibit important metalloenzymes containing Ni(II) and Zn(II). As urease inhibitors, HAs were first described by Kobashi et al. in 1962. Since then, studies showing their potential application in the treatment of infections caused by ureolytic microorganisms, such as Helicobacter pylori and Proteus mirabilis, have been reported. In this context, the present work comprises the structural planning, synthesis, and evaluation of the urease inhibitory activity of a series of molecular hybrids of hydroxamic acids with Michael acceptors. Molecular hybridization aims to maximize inhibitory effects, as Michael acceptors also exhibit recognized anti-ureolytic activity. The synthesized compounds proved to be potent urease inhibitors with IC50 values ranging from 12.8-3.8 μM, observing that activity was proportional to the electrophilicity of the β carbon. Enzyme kinetic studies showed that the hydroxamic acid-Michael acceptor hybrids are mixed-type inhibitors, while the absence of the Michael acceptor moiety results in competitive inhibition. Biophysical interaction studies suggest that the hydroxamic acid interacts with the enzyme's active site while the Michael acceptor binds to an allosteric site, a nearby cysteine residue near the catalytic center.