New series of monoamidoxime derivatives displaying versatile antiparasitic activity

  • Eur J Med Chem. 2014 Nov 24:87:440-53. doi: 10.1016/j.ejmech.2014.07.113.
Clémence Tabélé  1 ,  Anita Cohen  2 ,  Christophe Curti  1 ,  Ahlem Bouhlel  1 ,  Sébastien Hutter  2 ,  Vincent Remusat  1 ,  Nicolas Primas  1 ,  Thierry Terme  1 ,  Nadine Azas  2 ,  Patrice Vanelle  3
Affiliations
  • 1. Aix-Marseille Université, CNRS, ICR, UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin, CS30064, 13385 Marseille Cedex 05, France.
  • 2. Aix-Marseille Université, IRD, IRBA, Université de Montpellier 1, IP-TPT UMR_MD 3, Infections Parasitaires, Transmission, Pharmacologie et Thérapeutique, Faculté de Pharmacie, 27 Boulevard Jean Moulin, CS30064, 13385 Marseille Cedex 05, France.
  • 3. Aix-Marseille Université, CNRS, ICR, UMR 7273, Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, 27 Boulevard Jean Moulin, CS30064, 13385 Marseille Cedex 05, France. Electronic address: [email protected].
PMID: 25282267 DOI: 10.1016/j.ejmech.2014.07.113
Abstract

Following the promising antileishmanial results previously obtained in monoamidoxime series, a new series of derivatives was synthesized using manganese(III) acetate, Wittig reactions and Suzuki-Miyaura cross coupling reactions. Pharmacomodulation in R(1), R(2) or R(3) substituents on the amidoxime structure is shown to influence antiprotozoan activity in vitro: a monosubstituted phenyl group in R1 (32-35) led to an activity against Leishmania donovani promastigotes (32, IC50 = 9.16 μM), whereas a polysubstituted group (36-37) led to an activity against Plasmodium falciparum (36, IC50 = 2.76 μM). Modulating chemical substituents in R(2) and R(3) only influenced the antiplasmodial activity in vitro. This suggests that the amidoxime scaffold has properties that could make it a promising new antiparasitic pharmacophore.

Keywords
Amidoximes; Antiprotozoan activity in vitro; Cytotoxicity in vitro; Dihydrofuran; Manganese(III) acetate; Palladium-catalyzed coupling reactions; Pharmacomodulation.