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Synthesis and biological evaluation of novel quinoline-piperidine scaffolds as antiplasmodium agents

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Abstract
The parasitic disease malaria places almost half of the world's population at risk of infection and is responsible for more than 400,000 deaths each year. The first-line treatment, artemisinin combination therapies (ACT) regimen, is under threat due to emerging resistance of Plasmodium falciparum strains in e.g. the Mekong delta. Therefore, the development of new antimalarial agents is crucial in order to circumvent the growing resistance. Chloroquine, the long-established antimalarial drug, still serves as model compound for the design of new quinoline analogues, resulting in numerous new active derivatives against chloroquine-resistant P. falciparum strains over the past twenty years. In this work, a set of functionalized quinoline analogues, decorated with a modified piperidine-containing side chain, was synthesized. Both amino- and (aminomethyl)quinolines were prepared, resulting in a total of 18 novel quinoline-piperidine conjugates representing four different chemical series. Evaluation of their in vitro antiplasmodium activity against a CQ-sensitive (NF54) and a CQ-resistant (K1) strain of P. falciparum unveiled highly potent activities in the nanomolar range against both strains for five 4-aminoquinoline derivatives. Moreover, no cytotoxicity was observed for all active compounds at the maximum concentration tested. These five new aminoquinoline hit structures are therefore of considerable value for antimalarial research and have the potency to be transformed into novel antimalarial agents upon further hit-to-lead optimization studies.
Keywords
Organic Chemistry, Pharmacology, Drug Discovery, General Medicine, Quinolines, Piperidines, Malaria, Chloroquine, Plasmodium, MALARIA PARASITES, CHLOROQUINE RESISTANCE, RING TRANSFORMATION, ANTIMALARIAL, MECHANISMS, AZIRIDINES, ASSAY, 4-AMINOQUINOLINES, REARRANGEMENT, HEMATIN

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MLA
Van de Walle, Tim, et al. “Synthesis and Biological Evaluation of Novel Quinoline-Piperidine Scaffolds as Antiplasmodium Agents.” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 198, 2020, doi:10.1016/j.ejmech.2020.112330.
APA
Van de Walle, T., Boone, M., Van Puyvelde, J., Combrinck, J., Smith, P. J., Chibale, K., … D’hooghe, M. (2020). Synthesis and biological evaluation of novel quinoline-piperidine scaffolds as antiplasmodium agents. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 198. https://doi.org/10.1016/j.ejmech.2020.112330
Chicago author-date
Van de Walle, Tim, Maya Boone, Julie Van Puyvelde, Jill Combrinck, Peter J. Smith, Kelly Chibale, Sven Mangelinckx, and Matthias D’hooghe. 2020. “Synthesis and Biological Evaluation of Novel Quinoline-Piperidine Scaffolds as Antiplasmodium Agents.” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 198. https://doi.org/10.1016/j.ejmech.2020.112330.
Chicago author-date (all authors)
Van de Walle, Tim, Maya Boone, Julie Van Puyvelde, Jill Combrinck, Peter J. Smith, Kelly Chibale, Sven Mangelinckx, and Matthias D’hooghe. 2020. “Synthesis and Biological Evaluation of Novel Quinoline-Piperidine Scaffolds as Antiplasmodium Agents.” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 198. doi:10.1016/j.ejmech.2020.112330.
Vancouver
1.
Van de Walle T, Boone M, Van Puyvelde J, Combrinck J, Smith PJ, Chibale K, et al. Synthesis and biological evaluation of novel quinoline-piperidine scaffolds as antiplasmodium agents. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. 2020;198.
IEEE
[1]
T. Van de Walle et al., “Synthesis and biological evaluation of novel quinoline-piperidine scaffolds as antiplasmodium agents,” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 198, 2020.
@article{8691843,
  abstract     = {{The parasitic disease malaria places almost half of the world's population at risk of infection and is responsible for more than 400,000 deaths each year. The first-line treatment, artemisinin combination therapies (ACT) regimen, is under threat due to emerging resistance of Plasmodium falciparum strains in e.g. the Mekong delta. Therefore, the development of new antimalarial agents is crucial in order to circumvent the growing resistance. Chloroquine, the long-established antimalarial drug, still serves as model compound for the design of new quinoline analogues, resulting in numerous new active derivatives against chloroquine-resistant P. falciparum strains over the past twenty years. In this work, a set of functionalized quinoline analogues, decorated with a modified piperidine-containing side chain, was synthesized. Both amino- and (aminomethyl)quinolines were prepared, resulting in a total of 18 novel quinoline-piperidine conjugates representing four different chemical series. Evaluation of their in vitro antiplasmodium activity against a CQ-sensitive (NF54) and a CQ-resistant (K1) strain of P. falciparum unveiled highly potent activities in the nanomolar range against both strains for five 4-aminoquinoline derivatives. Moreover, no cytotoxicity was observed for all active compounds at the maximum concentration tested. These five new aminoquinoline hit structures are therefore of considerable value for antimalarial research and have the potency to be transformed into novel antimalarial agents upon further hit-to-lead optimization studies.}},
  articleno    = {{112330}},
  author       = {{Van de Walle, Tim and Boone, Maya and Van Puyvelde, Julie and Combrinck, Jill and Smith, Peter J. and Chibale, Kelly and Mangelinckx, Sven and D'hooghe, Matthias}},
  issn         = {{0223-5234}},
  journal      = {{EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY}},
  keywords     = {{Organic Chemistry,Pharmacology,Drug Discovery,General Medicine,Quinolines,Piperidines,Malaria,Chloroquine,Plasmodium,MALARIA PARASITES,CHLOROQUINE RESISTANCE,RING TRANSFORMATION,ANTIMALARIAL,MECHANISMS,AZIRIDINES,ASSAY,4-AMINOQUINOLINES,REARRANGEMENT,HEMATIN}},
  language     = {{eng}},
  pages        = {{13}},
  title        = {{Synthesis and biological evaluation of novel quinoline-piperidine scaffolds as antiplasmodium agents}},
  url          = {{http://dx.doi.org/10.1016/j.ejmech.2020.112330}},
  volume       = {{198}},
  year         = {{2020}},
}

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