Synthesis and structure-activity relationships of new chiral spiro-β-lactams highly active against HIV-1 and Plasmodium

被引:24
作者
Alves, Nuno Guerreiro [1 ,2 ]
Bartolo, Ines [3 ]
Alves, Americo J. S. [1 ,2 ]
Fontinha, Diana [4 ]
Francisco, Denise [4 ]
Lopes, Susana M. M. [1 ,2 ]
Soares, Maria I. L. [1 ,2 ]
Simoes, Carlos J., V [1 ,2 ,5 ]
Prudencio, Miguel [4 ]
Taveira, Nuno [3 ,6 ]
Pinho e Melo, Teresa M. V. D. [1 ,2 ]
机构
[1] Univ Coimbra, Coimbra Chem Ctr, P-3004535 Coimbra, Portugal
[2] Univ Coimbra, Dept Chem, P-3004535 Coimbra, Portugal
[3] Univ Lisbon, Fac Farm, Inst Invest Med iMed ULisboa, Av Prof Gama Pinto, P-1649003 Lisbon, Portugal
[4] Univ Lisbon, Fac Med, Inst Med Mol Joao Lobo Antunes, Ave Prof Egas Moniz, P-1649028 Lisbon, Portugal
[5] Inst Pedro Nunes, BSIM Therapeut, Coimbra, Portugal
[6] Inst Univ Egas Moniz IUEM, Ctr Invest Interdisciplinar Egas Moniz CiiEM, Caparica, Portugal
关键词
Anti-HIV agents; Antiplasmodial agents; Spiro-penicillanates; beta-Lactams; Spirocyclic compounds; Spiro-3H-pyrazole-beta-lactams; Spirocyclopentenyl-beta-lactams; 1,3-Dipolar cycloaddition; Phosphane-catalyzed [3+2] annulations; Allenes; 2-Butynoates; CONFORMER GENERATION; CYCLOADDITIONS; REGIOSELECTIVITY; 2-BUTYNOATES; MECHANISM; PEPTIDE;
D O I
10.1016/j.ejmech.2021.113439
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The synthesis and antimicrobial activity of new spiro-beta-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-beta-lactams synthesized were assayed for their in vitro activity against HIV-1, providing relevant structure-activity relationship information. Among the tested compounds, two spirocyclopentenyl-beta-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. (C) 2021 Elsevier Masson SAS. All rights reserved.
引用
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页数:16
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