A carregar...
Projeto de investigação
Broadening the spectrum of spito-B-lactams antiviral activity: from new targets identification to the discovery of new compounds with anti-influenza activity.
Financiador
Autores
Publicações
Synthesis and structure-activity relationships of new chiral spiro-ß-lactams highly active against HIV-1 and Plasmodium
Publication . G. Alves, Nuno; Bártolo, Inês; Alves, Américo; Fontinha, Diana; Francisco, Denise; Lopes, Susana M. M.; Soares, Maria I. L.; Simões, Carlos J. V.; Prudêncio, Miguel; Taveira, Nuno; Melo, Teresa M. V. D. Pinho E
The synthesis and antimicrobial activity of new spiro-β-lactams is reported. The design of the new molecules was based on the structural modulation of two previously identified lead spiro-penicillanates with dual activity against HIV and Plasmodium. The spiro-β-lactams synthesized were assayed for their in vitro activity against HIV-1, providing relevant structure-activity relationship information. Among the tested compounds, two spirocyclopentenyl-β-lactams were identified as having remarkable nanomolar activity against HIV-1. Additionally, the same molecules showed promising antiplasmodial activity, inhibiting both the hepatic and blood stages of Plasmodium infection.
Spiro-Lactams as Novel Antimicrobial Agents
Publication . Alves, Américo; G. Alves, Nuno; Caratão, Cátia; Esteves, Margarida; Fontinha, Diana; Bártolo, Inês; Soares, Maria I. L.; Lopes, Susana M. M.; Prudêncio, Miguel; Taveira, Nuno; Melo, Teresa M. V. D. Pinho E
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.
Spiro-ß-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium
Publication . Bártolo, Inês; Santos, Bruna S.; Fontinha, Diana; Machado, Marta; Francisco, Denise; Sepodes, Bruno; Rocha, Joao; Mota-Filipe, Hélder; Pinto, Rui; Figueira, Maria-Eduardo; Barroso, Helena; Nascimento, Teresa; Matos, António P. Alves de; Alves, Américo; Alves, Nuno G.; Simões, Carlos J. V.; Prudêncio, Miguel; Melo, Teresa M. V. D. Pinho E; Taveira, Nuno
The high burden of malaria and HIV/AIDS prevents economic and social progress in developing countries. A continuing need exists for development of novel drugs and treatment regimens for both diseases in order to address the tolerability and long-term safety concerns associated with current treatment options and the emergence of drug resistance. We describe new spiro-β-lactam derivatives with potent (nM) activity against HIV and Plasmodium and no activity against bacteria and yeast. The best performing molecule of the series, BSS-730A, inhibited both HIV-1 and HIV-2 replication with an IC50 of 13 ± 9.59 nM and P. berghei hepatic infection with an IC50 of 0.55 ± 0.14 μM with a clear impact on parasite development. BSS-730A was also active against the erythrocytic stages of P. falciparum, with an estimated IC50 of 0.43 ± 0.04 μM. Time-of-addition studies showed that BSS-730A potentially affects all stages of the HIV replicative cycle, suggesting a complex mechanism of action. BSS-730A was active against multidrug-resistant HIV isolates, with a median 2.4-fold higher IC50 relative to control isolates. BSS-730A was equally active against R5 and X4 HIV isolates and displayed strong synergism with the entry inhibitor AMD3100. BSS-730A is a promising candidate for development as a potential therapeutic and/or prophylactic agent against HIV and Plasmodium.
Unidades organizacionais
Descrição
Palavras-chave
Contribuidores
Financiadores
Entidade financiadora
Fundação para a Ciência e a Tecnologia
Programa de financiamento
Número da atribuição
PD/BD/135287/2017