2. Academic Validation
  3. Design, synthesis, and characterization of novel aminoalcohol quinolines with strong in vitro antimalarial activity

Design, synthesis, and characterization of novel aminoalcohol quinolines with strong in vitro antimalarial activity

  • Eur J Med Chem. 2022 Jan 15;228:113981. doi: 10.1016/j.ejmech.2021.113981.
A Dassonville-Klimpt 1,  J Schneider 2,  C Damiani 2,  C Tisnerat 2,  A Cohen 3,  N Azas 3,  M Marchivie 4,  J Guillon 5,  C Mullié 2,  P Agnamey 2,  Anne Totet 2,  J Dormoi 6,  N Taudon 7,  B Pradines 8,  P Sonnet 9
Affiliations

Affiliations

  • 1 Université de Picardie Jules Verne, AGIR, UFR de Pharmacie, Amiens, UR, 4294, France. Electronic address: alexandra.dassonville@u-picardie.fr.
  • 2 Université de Picardie Jules Verne, AGIR, UFR de Pharmacie, Amiens, UR, 4294, France.
  • 3 Université Aix-Marseille, IRD, AP-HM, SSA, VITROME, IHU Méditerranée Infection, Marseille, France.
  • 4 CNRS, Univ. Bordeaux, Bordeaux INP, ICMCB, UMR 5026, F- 33600 Pessac, France.
  • 5 Université de Bordeaux, Laboratoire ARNA, UFR des Sciences Pharmaceutiques, Bordeaux, France; INSERM U1212, UMR CNRS 5320, Laboratoire ARNA, Bordeaux, France.
  • 6 Unité parasitologie et entomologie, Département de microbiologie et de maladies infectieuses, Institut de recherche biomédicale des armées, Marseille, France; Aix-Marseille Univ, IRD, SSA, AP-HM, VITROME, Marseille, France; IHU Méditerranée Infection, Marseille, France.
  • 7 Unité de Développements Analytiques et Bioanalyse, IRBA, Brétigny-sur-Orge, France.
  • 8 Unité parasitologie et entomologie, Département de microbiologie et de maladies infectieuses, Institut de recherche biomédicale des armées, Marseille, France; Aix-Marseille Univ, IRD, SSA, AP-HM, VITROME, Marseille, France; IHU Méditerranée Infection, Marseille, France; Centre national de référence du paludisme, Marseille, France.
  • 9 Université de Picardie Jules Verne, AGIR, UFR de Pharmacie, Amiens, UR, 4294, France. Electronic address: pascal.sonnet@u-picardie.fr.
PMID: 34782182 DOI: 10.1016/j.ejmech.2021.113981
Abstract

Malaria is the fifth most lethal parasitic infections in the world. Herein, five new series of aminoalcohol quinolines including fifty-two compounds were designed, synthesized and evaluated in vitro against Pf3D7 and PfW2 strains. Among them, fourteen displayed IC50 values below or near of 50.0 nM whatever the strain with selectivity index often superior to 100.17b was found as a promising antimalarial candidate with IC50 values of 14.9 nM and 11.0 nM against respectively Pf3D7 and PfW2 and a selectivity index higher than 770 whatever the cell line is. Further experiments were achieved to confirm the safety and to establish the preliminary ADMET profile of compound 17b before the in vivo study performed on a mouse model of P. berghei ANKA Infection. The overall data of this study allowed to establish new structure-activity relationships and the development of novel agents with improved pharmacokinetic properties.

Keywords

Aminoalcohol quinolines; Antimalarial drug resistance; In vivo; Malaria; Mefloquine analogs; P. falciparum; in vitro.

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