Spiro-β-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium.

Autor:	Bártolo I; Instituto de investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal., Santos BS; Coimbra Chemistry Centre (CQC), Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal., Fontinha D; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1648-028 Lisboa, Portugal., Machado M; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1648-028 Lisboa, Portugal., Francisco D; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1648-028 Lisboa, Portugal., Sepodes B; Instituto de investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal., Rocha J; Instituto de investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal., Mota-Filipe H; Instituto de investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal., Pinto R; Instituto de investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal., Figueira ME; Instituto de investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal., Barroso H; Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Instituto Universitário Egas Moniz, Quinta da Granja, 2829-511 Monte da Caparica, Portugal., Nascimento T; Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Instituto Universitário Egas Moniz, Quinta da Granja, 2829-511 Monte da Caparica, Portugal., Alves de Matos AP; Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Instituto Universitário Egas Moniz, Quinta da Granja, 2829-511 Monte da Caparica, Portugal., Alves AJS; Coimbra Chemistry Centre (CQC), Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal., Alves NG; Coimbra Chemistry Centre (CQC), Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal., Simões CJV; Coimbra Chemistry Centre (CQC), Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal., Prudêncio M; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1648-028 Lisboa, Portugal., Pinho E Melo TMVD; Coimbra Chemistry Centre (CQC), Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal., Taveira N; Instituto de investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.; Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Instituto Universitário Egas Moniz, Quinta da Granja, 2829-511 Monte da Caparica, Portugal.
Jazyk:	angličtina
Zdroj:	ACS infectious diseases [ACS Infect Dis] 2021 Feb 12; Vol. 7 (2), pp. 421-434. Date of Electronic Publication: 2021 Jan 04.
DOI:	10.1021/acsinfecdis.0c00768
Abstrakt:	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 IC 50 of 13 ± 9.59 nM and P. berghei hepatic infection with an IC 50 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 IC 50 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 IC 50 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 .
Databáze:	MEDLINE
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