BENTZINGER, Guillaume; PAIR, Etienne; GUILLON, Jean; MARCHIVIE, Mathieu; MULLIÉ, Catherine; AGNAMEY, Patrice; DASSONVILLE-KLIMPT, Alexandra; SONNET, Pascal

doi:10.1016/j.tet.2020.131088

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BENTZINGER, Guillaume
Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 [AGIR ]

PAIR, Etienne
Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 [AGIR ]

GUILLON, Jean
Acides Nucléiques : Régulations Naturelle et Artificielle [ARNA]

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Tetrahedron. 2020-04, vol. 76, n° 15, p. 131088 (10 p.)

Elsevier

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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.< Réduire

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Malaria P. falciparum

Arylaminoalcohols

Enpiroline

Asymmetric synthesis

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Enantiopure substituted pyridines as promising antimalarial drug candidates

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