Discovery of a new antileishmanial hit in 8-nitroquinoline series

作者：Paloque Lucie; Verhaeghe Pierre; Casanova Magali; Castera Ducros Caroline; Dumetre Aurelien; Mbatchi Litaty; Hutter Sebastien; Kraiem M' Rabet Manel; Laget Michele; Remusat Vincent; Rault Sylvain; Rathelot Pascal; Azas Nadine; Vanelle Patrice^*

来源：European Journal of Medicinal Chemistry, 2012, 54: 75-86.

DOI：10.1016/j.ejmech.2012.04.029

• 8-Nitroquinoline
• Visceral leishmaniasis
• Leishmania donovani
• Leishmania infantum
• Promastigotes
• Amastigotes
• hepG2 cytotoxicity
• Selectivity index

A series of nitrated 2-substituted-quinolines was synthesized and evaluated in vitro toward Leishmania donovani promastigotes. In parallel, the in vitro cytotoxicity of these molecules was assessed on the murine J774 and human HepG2 cell lines. Thus, a very promising antileishmanial hit molecule was identified (compound 21), displaying an IC50 value of 6.6 mu M and CC50 values %26gt;= 100 mu M, conferring quite good selectivity index to this molecule, in comparison with 3 drug-compounds of reference (amphotericin B, miltefosine and pentamidine). Compound 21 also appears as an efficient in vitro antileishmanial molecule against both Leishmania infantum promastigotes and the intracellular L. donovani amastigotes (respective IC50 = 7.6 and 6.5 mu M). Moreover, hit quinoline 21 does not show neither significant antiplasmodial nor antitoxoplasmic in vitro activity and though, presents a selective antileishmanial activity. Finally, a structure activity relationships study enabled to define precisely the antileishmanial pharmacophore based on this nitroquinoline scaffold: 2-hydroxy-8-nitroquinoline.

• 出版日期2012-8