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|Title:||Spiro-Lactams as Novel Antimicrobial Agents||Authors:||Alves, Américo J. S.
Alves, Nuno G.
Caratão, Cátia C.
Esteves, Margarida I. M.
Soares, Maria I. L.
Lopes, Susana M. M.
Melo, Teresa M. V. D. Pinho e
|Keywords:||5-Oxohexahydropyrrolo[2,1-b]thiazoles; Anti-HIV Agents; Antiplasmodial Agents; Diazo Compounds; Dipolar Cycloaddition; Spiro-penicillanate; Spiro-γ-lactams||Issue Date:||2020||Publisher:||Bentham Science||Project:||UID/QUI/00313/2019
|Serial title, monograph or event:||Current Topics in Medicinal Chemistry||Volume:||20||Issue:||2||Abstract:||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.||URI:||http://hdl.handle.net/10316/90921||ISSN:||15680266||DOI:||10.2174/1568026619666191105110049||Rights:||embargoedAccess|
|Appears in Collections:||I&D CQC - Artigos em Revistas Internacionais|
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