Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties.
Fiche publication
Date publication
janvier 2017
Journal
Molecules (Basel, Switzerland)
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DAVIOUD-CHARVET Elisabeth , Dr ELHABIRI Mourad
Tous les auteurs :
Urgin K, Jida M, Ehrhardt K, Müller T, Lanzer M, Maes L, Elhabiri M, Davioud-Charvet E
Lien Pubmed
Résumé
With the aim of increasing the structural diversity on the early antimalarial drug plasmodione, an efficient and versatile procedure to prepare a series of biaryl- and -arylalkylamines as plasmodione analogues is described. Using the naturally occurring and commercially available menadione as starting material, a 2-step sequence using a Kochi-Anderson reaction and subsequent Pd-catalyzed Suzuki-Miyaura coupling was developed to prepare three representative biphenyl derivatives in good yields for antimalarial evaluation. In addition, synthetic methodologies to afford 3-benzylmenadione derivatives bearing a terminal -(Me)₂ or -(Et)₂ in different positions (, and on the aryl ring of the benzylic chain of plasmodione were investigated through reductive amination was used as the optimal route to prepare these protonable -arylalkylamine privileged scaffolds. The antimalarial activities were evaluated and discussed in light of their physicochemical properties. Among the newly synthesized compounds, the -position of the substituent remains the most favourable position on the benzyl chain and the carbamate -HBoc was found active both in vitro (42 nM versus 29 nM for plasmodione) and in vivo in -infected mice. The measured acido-basic features of these new molecules support the cytosol-food vacuole shuttling properties of non-protonable plasmodione derivatives essential for redox-cycling. These findings may be useful in antimalarial drug optimization.
Mots clés
Amines, administration & dosage, Animals, Antimalarials, administration & dosage, Combinatorial Chemistry Techniques, Malaria, drug therapy, Mice, Molecular Structure, Oxidation-Reduction, Plasmodium berghei, drug effects, Structure-Activity Relationship, Vitamin K 3, analogs & derivatives
Référence
Molecules. 2017 Jan 19;22(1):