Journal
TETRAHEDRON
Volume 76, Issue 15, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tet.2020.131088
Keywords
Malaria; P. falciparum; Arylaminoalcohols; Enpiroline; Asymmetric synthesis
Categories
Funding
- ANR Astrid [ANR-12-STR-003]
- region Picardie
- SATT Nord
- DGA (Direction Generale de l'Armement, Ministere de la Defense, France)
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We describe the enantioselective synthesis and biological evaluation of 4-(2-amino-l-hydroxyethyl) pyridines (4 AHPs) as new antimalarial drug candidates. In particular, two routes to obtain the key-intermediate 4-vinyl-pyridine were studied. These routes are based on a Krohnke-type cyclization or on metal-catalyzed reactions. The Krohnke-type cyclization route is faster but only efficient at low scale since this pathway involves a Wittig reaction that requires severe temperature-control. Consequently, we designed a second route based on metal-catalyzed reactions. This way is longer but the 4-vinyl-pyridine can be obtained on a 5 g scale at least. Finally, a regioselective S(N)2 ring-opening of enantiopure epoxides by alkyl primary amines allowed the synthesis of eight 4-AHPs with global yields up to 41%. These compounds show strong in vitro antimalarial activity against P. falciparum strains and are more active that chloroquine and mefloquine. These results demonstrate that 4-AHPs are promising antimalarial drug candidates. (C) 2020 Elsevier Ltd. All rights reserved.
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