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Synthesis and in vitro evaluation of new 5-substituted 6-nitroimidazooxazoles as antikinetoplastid agents

Abstract : In continuation of our pharmacomodulation work on the nitroimidazooxazole series, we report the synthesis of new 5-substituted 6-nitroimidazooxazole derivatives. Our aim was to evaluate how func-tionalization of the 5-position of the 6-nitroimidazooxazole scaffold affects antileishmanial and anti-trypanosomal in vitro activities. Twenty-one original compounds were synthesized and evaluated for their in vitro antileishmanial (L. donovani) and antitrypanosomal (T. cruzi) properties. Pallado-catalyzed cross-coupling reactions were used to introduce an aryl or ethynyl aryl substituent in 5-position from a 5-brominated-6-nitroimidazooxazole starting product. Unfortunately, the first series of compounds bearing an aryl group in 5-position presented limited in vitro activities against L. donovani and T. cruzi, with IC 50 > 10 mM (vs 0.18 mM and 2.31 mM for the reference drugs amphotericin B and benznidazole respectively). Interestingly, the second series of compounds bearing an ethynyl aryl substituent in 5-position showed more promising, particularly against T. cruzi. Compounds 6a, 6b, 6c, 6g and 6h had better activity than the reference drug benznidazole (0.92 mM IC 50 2.18 mM vs IC 50 ¼ 2.31 mM), whereas the non-functionalized 2-methyl-6-nitro-2,3-dihydroimidazo [2,1-b]oxazole 2 was not active against T. cruzi (IC 50 > 10 mM).
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Submitted on : Monday, April 6, 2020 - 12:07:57 PM
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Fanny Mathias, Anita Cohen, Youssef Kabri, Núria Waddington Negrão, Maxime Crozet, et al.. Synthesis and in vitro evaluation of new 5-substituted 6-nitroimidazooxazoles as antikinetoplastid agents. European Journal of Medicinal Chemistry, Elsevier, 2020, 191, pp.112146. ⟨10.1016/j.ejmech.2020.112146⟩. ⟨hal-02504497⟩

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