Details

Autor(en) / Beteiligte

• Van de Walle, Tim
• Boone, Maya
• Van Puyvelde, Julie
• Combrinck, Jill
• Smith, Peter J.
• Chibale, Kelly
• Mangelinckx, Sven
• D’hooghe, Matthias

Titel

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

Ist Teil von

• European journal of medicinal chemistry, 2020-07, Vol.198, p.112330, Article 112330

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2020

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals

Beschreibungen/Notizen

• 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. [Display omitted] •Four different series of new quinoline analogues decorated with a piperidine-containing side chain were synthesized.•Antiplasmodium assessments in NF54 (CQ-sensitive) and K1 (CQ-resistant) strains of P. falciparum were performed.•Five 4-aminoquinoline-piperidine compounds displayed nanomolar activities against both NF54 and K1 and no CHO toxicity.