Spiro-β-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium
Inês Bártolo, Bruna S. Santos, Diana Fontinha, Marta Machado, Denise Francisco, Bruno Sepodes, João Rocha, Hélder Mota‐Filipe, Rui Pinto, Maria Eduardo Figueira, Helena Barroso, Teresa Nascimento, António Matos, Américo J. S. Alves, Nuno G. Alves, Carlos J. V. Simões, Miguel Prudêncio, Teresa M. V. D. Pinho e Melo, Nuno Taveira
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.