Novel enantiopure pyridine-based aminoalcohols as promising antimalarial candidates

Abstract

Malaria is the fifth deadliest parasitic infection in the world. Herein, three new series of pyridine-based amino alcohols including twenty compounds were designed and synthesized using a short and optimized asymmetric synthetic route. Following in vitro evaluation of their activity against Pf3D7 and PfW2 strains and assessment of their cytotoxicity, the pharmacokinetic profiles of the fourteen compounds exhibiting selectivity index values above 100 were characterized. After in vivo acute toxicity studies of eleven pyridine-based amino alcohols, five compounds were selected for efficacy evaluation in a mouse model of Plasmodium berghei ANKA infection at 5 mg/kg. Further studies were then conducted to complete their safety profiles. Overall, 10a was identified as the most promising candidate. Treatment with compound 10a at 5 mg/kg resulted in a marked reduction in parasitemia, and a higher survival rate compared with mefloquine at 10 mg/kg. Finally, regarding interactions toward a panel of central nervous system-relevant targets, compound 10a exhibited a lower predicted potential to disrupt central nervous system function, compared with the reference compounds mefloquine and enpiroline.

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BibTeX RIS

BibTeX

@article{herrero2026novel,
  title = {{Novel enantiopure pyridine-based aminoalcohols as promising antimalarial candidates}},
  author = {Aurélie Herrero and Camille Tisnerat and Guillaume Bentzinger and Etienne Pair and Anne Bouchut and Romain Mustière and Christophe Landry and Fabien Gosselet and Catherine Mullié and Patrice Agnamey and Nicolas Taudon and Bruno Pradines and Alexandra Dassonville-Klimpt and Pascal Sonnet},
  journal = {European Journal of Medicinal Chemistry},
  year = {2026},
  month = oct,
  doi = {10.1016/j.ejmech.2026.119349},
  url = {https://u-picardie.hal.science/hal-05766816v1},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - Novel enantiopure pyridine-based aminoalcohols as promising antimalarial candidates
AU  - Aurélie Herrero
AU  - Camille Tisnerat
AU  - Guillaume Bentzinger
AU  - Etienne Pair
AU  - Anne Bouchut
AU  - Romain Mustière
AU  - Christophe Landry
AU  - Fabien Gosselet
AU  - Catherine Mullié
AU  - Patrice Agnamey
AU  - Nicolas Taudon
AU  - Bruno Pradines
AU  - Alexandra Dassonville-Klimpt
AU  - Pascal Sonnet
PY  - 2026
DA  - 2026/10/30
JO  - European Journal of Medicinal Chemistry
DO  - 10.1016/j.ejmech.2026.119349
UR  - https://u-picardie.hal.science/hal-05766816v1
AB  - Malaria is the fifth deadliest parasitic infection in the world. Herein, three new series of pyridine-based amino alcohols including twenty compounds were designed and synthesized using a short and optimized asymmetric synthetic route. Following in vitro evaluation of their activity against Pf3D7 and PfW2 strains and assessment of their cytotoxicity, the pharmacokinetic profiles of the fourteen compounds exhibiting selectivity index values above 100 were characterized. After in vivo acute toxicity studies of eleven pyridine-based amino alcohols, five compounds were selected for efficacy evaluation in a mouse model of Plasmodium berghei ANKA infection at 5 mg/kg. Further studies were then conducted to complete their safety profiles. Overall, 10a was identified as the most promising candidate. Treatment with compound 10a at 5 mg/kg resulted in a marked reduction in parasitemia, and a higher survival rate compared with mefloquine at 10 mg/kg. Finally, regarding interactions toward a panel of central nervous system-relevant targets, compound 10a exhibited a lower predicted potential to disrupt central nervous system function, compared with the reference compounds mefloquine and enpiroline.
SN  - 0223-5234
SN  - 1768-3254
ER  -

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