Synthesis and biological evaluation of novel quinoline-piperidine scaffolds as antiplasmodium agents
0301 basic medicine
Plasmodium
ANTIMALARIAL
Plasmodium falciparum
Drug Resistance
RING TRANSFORMATION
AZIRIDINES
Article
MECHANISMS
Antimalarials
Inhibitory Concentration 50
Structure-Activity Relationship
03 medical and health sciences
Parasitic Sensitivity Tests
Piperidines
MALARIA PARASITES
Drug Discovery
Medicine and Health Sciences
4-AMINOQUINOLINES
Humans
ASSAY
Malaria, Falciparum
Pharmacology
Molecular Structure
Organic Chemistry
REARRANGEMENT
Chloroquine
General Medicine
CHLOROQUINE RESISTANCE
Malaria
3. Good health
HEMATIN
Drug Design
Quinolines
DOI:
10.1016/j.ejmech.2020.112330
Publication Date:
2020-04-23T15:18:24Z
AUTHORS (8)
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.
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