Spiro-Lactams as Novel Antimicrobial Agents

• Autor(a) principal: Alves, Américo J. S.
• Data de Publicação: 2020
• Outros Autores: Alves, Nuno G., Caratão, Cátia C., Esteves, Margarida I. M., Fontinha, Diana, Bártolo, Inês, Soares, Maria I. L., Lopes, Susana M. M., Prudêncio, Miguel, Taveira, Nuno, Melo, Teresa M. V. D. Pinho e
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10316/90921; https://doi.org/10.2174/1568026619666191105110049
• topic: 5-Oxohexahydropyrrolo[2,1-b]thiazoles; Anti-HIV Agents; Antiplasmodial Agents; Diazo Compounds; Dipolar Cycloaddition; Spiro-penicillanate; Spiro-γ-lactams

Introduction: Structural modulation of previously identified lead spiro-β-lactams with antimicrobial activity was carried out. Objective: The main objective of this work was to synthesize and evaluate the biological activity of novel spiro-lactams based on previously identified lead compounds with antimicrobial activity. Methods: The target chiral spiro-γ-lactams were synthesized through 1,3-dipolar cycloaddition reaction of a diazo-γ-lactam with electron-deficient dipolarophiles. In vitro activity against HIV and Plasmodium of a wide range of spiro-β-lactams and spiro-γ-lactams was evaluated. Among these compounds, one derivative with good anti-HIV activity and two with promising antiplasmodial activity (IC50 < 3.5 µM) were identified. Results: A novel synthetic route to chiral spiro-γ-lactams has been established. The studied β- and γ- lactams were not cytotoxic, and three compounds with promising antimicrobial activity were identified, whose structural modulation may lead to new and more potent drugs. Conclusion: The designed structural modulation of biologically active spiro-β-lactams involved the replacement of the four-membered β-lactam ring by a five-membered γ-lactam ring. Although conformational and superimposition computational studies revealed no significant differences between β- and γ- lactam pharmacophoric features, the studied structural modulation did not lead to compounds with a similar biological profile. The observed results suggest that the β-lactamic core is a requirement for the activity against both HIV and Plasmodium.