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|Title:||Spiro-β-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium||Authors:||Bártolo, Inês
Santos, Bruna S
Figueira, Maria E.
Alves de Matos, António P.
Alves, Américo J. S.
Alves, Nuno G.
Simões, Carlos J. V.
Pinho e Melo, Teresa M. V. D.
|Keywords:||AIDS; BSS-730A; anti-HIV activity; antiplasmodial activity; malaria; spiro-β-lactams||Issue Date:||12-Feb-2021||Publisher:||ACS American Chemical Society||Project:||info:eu-repo/grantAgreement/FCT/UIDB/00313/2020
info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB/04138/2020/PT/Research Institute for Medicines
info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP/04138/2020/PT/Research Institute for Medicines
info:eu-repo/grantAgreement/FCT/9471 - RIDTI/PTDC/SAU-INF/29550/2017/PT/Enabling strategies for enhanced whole-sporozoite malaria vaccines
info:eu-repo/grantAgreement/FCT/OE/SFRH/BPD/76225/2011/PT/DESENVOLVIMENTO DE NOVOS MICROBICIDAS PARA PREVENIR A INFECÇÃO POR VIH
info:eu-repo/grantAgreement/FCT/POR_CENTRO/PD/BD/135287/2017/PT/Broadening the spectrum of spito-B-lactams antiviral activity: from new targets identification to the discovery of new compounds with anti-influenza activity.
info:eu-repo/grantAgreement/FCT/OE/SFRH/BD/128910/2017/PT/Novel spiro-lactams as new antimicrobial agents
|Serial title, monograph or event:||Infectious Diseases||Volume:||7||Issue:||2||Abstract:||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.||URI:||https://hdl.handle.net/10316/107452||ISSN:||2373-8227
|Appears in Collections:||I&D CQC - Artigos em Revistas Internacionais|
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