Original antileishmanial hits: Variations around amidoximes

In continuation to our previous findings on amidoximes' antiparasitic activities, a new series of 23 original derivatives was designed and obtained by convergent synthesis. First, new terminal alkenes were synthesized by cross-coupling reaction. Then, cyclization was performed between terminal...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2018-03, Vol.148, p.154-164
Main Authors: Tabélé, Clémence, Faiões, Viviane dos S., Grimaud, Fabien, Torres-Santos, Eduardo Caio, Khoumeri, Omar, Curti, Christophe, Vanelle, Patrice
Format: Article
Language:English
Subjects:
Amidoximes
Antiprotozoan activity in vitro
Chemical Sciences
Cytotoxicity in vitro
Dihydrofuran
Manganese(III) acetate
Pharmacomodulation
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Summary:In continuation to our previous findings on amidoximes' antiparasitic activities, a new series of 23 original derivatives was designed and obtained by convergent synthesis. First, new terminal alkenes were synthesized by cross-coupling reaction. Then, cyclization was performed between terminal alkenes and β-ketosulfones using manganese(III) acetate reactivity. Twenty-three amidoximes were tested for their in vitro activity against Leishmania amazonensis promastigotes and their toxicity on murine macrophages. Seven of the tested compounds exhibited an antileishmanial activity at lower than 10 μM with moderate to low toxicity. Six of these molecules showed activity at lower than 10 μM against promastigotes and toxicity at higher than 50 μM were selected and evaluated for their activity against intracellular Leishmania amazonensis amastigotes. Modulating chemical substituents in position 2 of dihydrofuran highly influenced their antileishmanial activities. The introduction of a methyl or trifluoromethyl group on the benzene ring of the benzyl group had a positive influence on activity without significantly increasing toxicity (52, 59, 60). [Display omitted] •Synthesis of amidoxime derivatives with valuable antileishmanial activities.•Radical synthesis of monoamidoxime derivatives mediated by manganese(III) acetate.•Cytotoxicity evaluated on murine macrophages.•Activity tested on Leishmania amazonensis promastigotes (strain MHOM/BR/77/LTB0016).•Activity tested on Leishmania amazonensis amastigotes.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2018.02.029