Novel enantiopure pyridine-based aminoalcohols as promising antimalarial candidates

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.