title: Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties.
abstract: 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- andN-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 -N(Me)₂ or -N(Et)₂ in different positions (ortho,metaandpara)on the aryl ring of the benzylic chain of plasmodione were investigated through reductive amination was used as the optimal route to prepare these protonableN-arylalkylamine privileged scaffolds. The antimalarial activities were evaluated and discussed in light of their physicochemical properties. Among the newly synthesized compounds, thepara-position of the substituent remains the most favourable position on the benzyl chain and the carbamate -NHBoc was found active both in vitro (42 nM versus 29 nM for plasmodione) and in vivo inPlasmodium berghei-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.
authors.affiliation: UMR 7509 CNRS-Université de Strasbourg, Bioorganic and Medicinal Chemistry Team, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, F-67087 Strasbourg, France. urginkarene@gmail.com.
authors.forename: Karène
authors.initials: K
authors.lastname: Urgin
authors.affiliation: UMR 7509 CNRS-Université de Strasbourg, Bioorganic and Medicinal Chemistry Team, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, F-67087 Strasbourg, France. mhmd_jida@yahoo.com.
authors.forename: Mouhamad
authors.initials: M
authors.lastname: Jida
authors.affiliation: UMR 7509 CNRS-Université de Strasbourg, Bioorganic and Medicinal Chemistry Team, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, F-67087 Strasbourg, France. ehrhardt.ka@gmail.com.|Zentrum für Infektiologie, Parasitologie, Universität Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany. ehrhardt.ka@gmail.com.
authors.forename: Katharina
authors.initials: K
authors.lastname: Ehrhardt
authors.affiliation: UMR 7509 CNRS-Université de Strasbourg, Bioorganic and Medicinal Chemistry Team, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, F-67087 Strasbourg, France. k.ehrhardt@ibmc-cnrs.unistra.fr.|Biochemie-Zentrum der Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany. k.ehrhardt@ibmc-cnrs.unistra.fr.
authors.forename: Tobias
authors.initials: T
authors.lastname: Müller
authors.affiliation: Zentrum für Infektiologie, Parasitologie, Universität Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany. michael.lanzer@med.uni-heidelberg.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Lanzer
authors.affiliation: Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium. louis.maes@uantwerpen.be.
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.affiliation: UMR 7509 CNRS-Université de Strasbourg, Bioorganic and Medicinal Chemistry Team, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, F-67087 Strasbourg, France. tobias_mueller79@web.de.
authors.forename: Mourad
authors.initials: M
authors.lastname: Elhabiri
authors.affiliation: UMR 7509 CNRS-Université de Strasbourg, Bioorganic and Medicinal Chemistry Team, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, F-67087 Strasbourg, France. elisabeth.davioud@unistra.fr.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Davioud-Charvet
mesh_terms: D000588:Amines / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D008288:Malaria / Q000188:drug therapy*; D051379:Mice; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010962:Plasmodium berghei / Q000187:drug effects; D013329:Structure-Activity Relationship; D024483:Vitamin K 3 / Q000031:analogs & derivatives
chemical_list: D000588:Amines; D000962:Antimalarials; D024483:Vitamin K 3
keywords: 1,4-naphthoquinone; N-arylalkylamines; Suzuki-Miyaura coupling; antimalarial; atovaquone; biaryls; menadione; plasmodione; redox-cycling; reductive amination