Antileishmanial activity, structure-activity relationship of series of 2-(trifluoromethyl)benzo[b][1,8]naphthyridin-4(1H)-ones.

Abstract

Trifluoromethyl-substituted quinolones and their analogues have emerged as an interesting platform in the last 6 years to design antiparasite agents. Many of their derivatives have been demonstrated to display excellent efficacy against flagellate parasites such as Plasmodium spp. In order to identify new analogues of trifluoromethyl-substituted quinolones to treat the American cutaneous leishmaniasis, we evaluated the antiproliferative activity of a series of 2-(trifluoromethyl)benzo[b]-[1,8]naphthyridin-4(1H)-ones on the Leishmania braziliensis and Leishmania mexicana parasites. The mentioned derivatives have never been evaluated against any parasite strain. In general, an in vitro evaluation on L.(L)mexicana and L.(V)braziliensis showed that L.(L)mexicana was more sensitive to the action of the compounds than L.(V)braziliensis, either in the promastigote or in the amastigote form. Five compounds exhibited moderate efficacy against L.(L)mexicana promastigotes, with IC50 values ranging from 9.65 to 14.76 µM. From the mentioned molecules, three compounds, 1e, 1f, and 1h, showed a discrete response against axenic and intracellular amastigotes, with LD50 values between 19 and 24 µM. Moreover, an in vitro evaluation was performed on an antimony-resistant amastigote strain and a human isolate amastigote strain. These three compounds showed discrete toxicity on peritoneal macrophages; however, their relatively good antiamastigote response compared to the drug glucantime promoted our trifluoromethyl-substituted benzo[b][1,8]naphthyridin-4(1H)-ones as a potential platform to design potent antileishmanial agents.