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Spiro-Lactams as Novel Antimicrobial Agents

[ Vol. 20 , Issue. 2 ]

Author(s):

Américo J.S. Alves, Nuno G. Alves, Cátia C. Caratão, Margarida I.M. Esteves, Diana Fontinha, Inês Bártolo, Maria I.L. Soares, Susana M.M. Lopes, Miguel Prudêncio, Nuno Taveira and Teresa M.V.D. Pinho e Melo*   Pages 140 - 152 ( 13 )

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.

Keywords:

Anti-HIV Agents, Antiplasmodial Agents, Spiro-γ-lactams, Spiro-penicillanate, 5-Oxohexahydropyrrolo[2, 1- b]thiazoles, Dipolar Cycloaddition, Diazo Compounds.

Affiliation:

CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Instituto de Medicina Molecular Joao Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028 Lisboa, Instituto de Investigacao do Medicamento (iMed.ULisboa), Faculdade de Farmacia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Instituto de Medicina Molecular Joao Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028 Lisboa, Instituto de Investigacao do Medicamento (iMed.ULisboa), Faculdade de Farmacia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, CQC and Department of Chemistry, University of Coimbra, 3004-535 Coimbra

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