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Molecules 2017, 22(1), 161; doi:10.3390/molecules22010161

Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties

1
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
2
Zentrum für Infektiologie, Parasitologie, Universität Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany
3
Biochemie-Zentrum der Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany
4
Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium
Present Address: INSERM U963/CNRS UPR9022, Institut de Biologie Moléculaire et Cellulaire, F-67084 Strasbourg, France.
*
Author to whom correspondence should be addressed.
Academic Editor: Thomas J. Schmidt
Received: 4 December 2016 / Revised: 8 January 2017 / Accepted: 12 January 2017 / Published: 19 January 2017

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- and N-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, meta and para) 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 N-arylalkylamine privileged scaffolds. The antimalarial activities were evaluated and discussed in light of their physicochemical properties. Among the newly synthesized compounds, the para-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 in Plasmodium 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. View Full-Text
Keywords: antimalarial; N-arylalkylamines; atovaquone; biaryls; menadione; 1,4-naphthoquinone; plasmodione; redox-cycling; reductive amination; Suzuki-Miyaura coupling antimalarial; N-arylalkylamines; atovaquone; biaryls; menadione; 1,4-naphthoquinone; plasmodione; redox-cycling; reductive amination; Suzuki-Miyaura coupling
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Urgin, K.; Jida, M.; Ehrhardt, K.; Müller, T.; Lanzer, M.; Maes, L.; Elhabiri, M.; Davioud-Charvet, E. Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties. Molecules 2017, 22, 161.

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