Enantiopure substituted pyridines as promising antimalarial drug candidates Article - Avril 2020

Guillaume Bentzinger, Etienne Pair, Jean Guillon, Mathieu Marchivie, Catherine Mullié, Patrice Agnamey, Alexandra Dassonville-Klimpt, Pascal Sonnet

Guillaume Bentzinger, Etienne Pair, Jean Guillon, Mathieu Marchivie, Catherine Mullié, Patrice Agnamey, Alexandra Dassonville-Klimpt, Pascal Sonnet, « Enantiopure substituted pyridines as promising antimalarial drug candidates  », Tetrahedron, avril 2020, 131088 (10 p.). ISSN 0040-4020

Abstract

We describe the enantioselective synthesis and biological evaluation of 4-(2-amino-1-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 Kröhnke-type cyclization or on metal-catalyzed reactions. The Kröhnke-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 SN2 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.

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