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.
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.
Equipe "Biomolécules Fluorées", Chimie Organique Bioorganique Réactivité et Analyses (COBRA), Institut de Recherche en Chimie Organique Fine de Rouen (IRCOF), UMR CNRS 6014, Université et Institut National des Sciences Appliquées (INSA) de Rouen, F-76821 Mont Saint Aignan Cedex, France.
Oleksandr S
OS
Kanishchev
Adeline
A
Lavoignat
Stéphane
S
Picot
Maurice
M
Médebielle
Jean-Philippe
JP
Bouillon
D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000634:Aminoquinolines; D000962:Antimalarials; D005663:Furans; D007769:Lactams; D007783:Lactones; D013438:Sulfhydryl Compounds; C001920:4-aminoquinoline; C039281:furan
Aminoquinoline; Antimalarial; Fluorine; Lactam; Lactone