Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties
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 start...
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MDPI AG
2017-01-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/22/1/161 |
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| author | Karène Urgin Mouhamad Jida Katharina Ehrhardt Tobias Müller Michael Lanzer Louis Maes Mourad Elhabiri Elisabeth Davioud-Charvet |
| author_facet | Karène Urgin Mouhamad Jida Katharina Ehrhardt Tobias Müller Michael Lanzer Louis Maes Mourad Elhabiri Elisabeth Davioud-Charvet |
| author_sort | Karène Urgin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T04:23:15Z |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-11T04:23:15Z |
| publishDate | 2017-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-53e798cd1fa64668a359e62aaa178e5c2022-12-22T01:21:03ZengMDPI AGMolecules1420-30492017-01-0122116110.3390/molecules22010161molecules22010161Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical PropertiesKarène Urgin0Mouhamad Jida1Katharina Ehrhardt2Tobias Müller3Michael Lanzer4Louis Maes5Mourad Elhabiri6Elisabeth Davioud-Charvet7UMR 7509 CNRS-Université de Strasbourg, Bioorganic and Medicinal Chemistry Team, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, F-67087 Strasbourg, FranceUMR 7509 CNRS-Université de Strasbourg, Bioorganic and Medicinal Chemistry Team, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, F-67087 Strasbourg, FranceUMR 7509 CNRS-Université de Strasbourg, Bioorganic and Medicinal Chemistry Team, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, F-67087 Strasbourg, FranceUMR 7509 CNRS-Université de Strasbourg, Bioorganic and Medicinal Chemistry Team, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, F-67087 Strasbourg, FranceZentrum für Infektiologie, Parasitologie, Universität Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, GermanyLaboratory of Microbiology, Parasitology and Hygiene (LMPH), Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, BelgiumUMR 7509 CNRS-Université de Strasbourg, Bioorganic and Medicinal Chemistry Team, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, F-67087 Strasbourg, FranceUMR 7509 CNRS-Université de Strasbourg, Bioorganic and Medicinal Chemistry Team, European School of Chemistry, Polymers and Materials (ECPM), 25, rue Becquerel, F-67087 Strasbourg, FranceWith 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.http://www.mdpi.com/1420-3049/22/1/161antimalarialN-arylalkylaminesatovaquonebiarylsmenadione1,4-naphthoquinoneplasmodioneredox-cyclingreductive aminationSuzuki-Miyaura coupling |
| spellingShingle | Karène Urgin Mouhamad Jida Katharina Ehrhardt Tobias Müller Michael Lanzer Louis Maes Mourad Elhabiri Elisabeth Davioud-Charvet Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties Molecules antimalarial N-arylalkylamines atovaquone biaryls menadione 1,4-naphthoquinone plasmodione redox-cycling reductive amination Suzuki-Miyaura coupling |
| title | Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties |
| title_full | Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties |
| title_fullStr | Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties |
| title_full_unstemmed | Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties |
| title_short | Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties |
| title_sort | pharmacomodulation of the antimalarial plasmodione synthesis of biaryl and n arylalkylamine analogues antimalarial activities and physicochemical properties |
| topic | antimalarial N-arylalkylamines atovaquone biaryls menadione 1,4-naphthoquinone plasmodione redox-cycling reductive amination Suzuki-Miyaura coupling |
| url | http://www.mdpi.com/1420-3049/22/1/161 |
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