New route to the 5-((arylthio- and heteroarylthio)methylene)-3-(2,2,2-trifluoroethyl)-furan-2(5H)-ones--key intermediates in the synthesis of 4-aminoquinoline γ-lactams as potent antimalarial compounds.

Oleksandr S. Kanishchev (1) , Adeline Lavoignat (2, 3) , Stéphane Picot (3, 2) , Maurice Médebielle (2) , J.-P. Bouillon (1)

1 COBRA - Chimie Organique et Bioorganique : Réactivité et Analyse
2 SMITh - Synthèse de Molécules d'Intérêt Thérapeutique
3 ICBMS - Institut de Chimie et Biochimie Moléculaires et Supramoléculaires

In this Letter we report on a multi-step synthesis of 5-((arylthio- and heteroarylthio)-methylene)-3-(2,2,2-trifluoroethyl)furan-2(5H)-ones starting from γ-keto thiolester or γ-keto carboxylic acid. The key intermediate γ-lactones were then reacted with 4-aminoquinoline-derived amines via ring opening-ring closure (RORC) process affording the corresponding γ-hydroxy-γ-lactams in moderate to good yields. In vitro antimalarial activity of the resulting new 4-aminoquinoline γ-lactams were evaluated against Plasmodium falciparum clones of variable sensitivity (3D7 and W2) and were found to be active in the range of 89-1600 nM with good resistance index and did not show cytotoxicity in vitro when tested against human umbilical vein endothelial cells (HUVEC) up to concentration of 50 μM.

Domaines: Chimie organique

Oleksandr S. Kanishchev, Adeline Lavoignat, Stéphane Picot, Maurice Médebielle, J.-P. Bouillon. New route to the 5-((arylthio- and heteroarylthio)methylene)-3-(2,2,2-trifluoroethyl)-furan-2(5H)-ones--key intermediates in the synthesis of 4-aminoquinoline γ-lactams as potent antimalarial compounds.. Bioorganic and Medicinal Chemistry Letters, 2013, 23 (22), pp.6167-6171. ⟨10.1016/j.bmcl.2013.08.108⟩. ⟨hal-00996647⟩