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Antileishmanial activity, structure–activity relationship of series of 2‐(trifluoromethyl)benzo[ b ][1,8]naphthyridin‐4(1 H )‐ones
Author(s) -
Romero Angel H.,
López Simon E.,
Rodríguez Noris,
Oviedo Henry
Publication year - 2018
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201800094
Subject(s) - amastigote , axenic , trifluoromethyl , in vitro , chemistry , leishmania mexicana , leishmania braziliensis , stereochemistry , leishmania , pharmacology , microbiology and biotechnology , leishmaniasis , biology , cutaneous leishmaniasis , biochemistry , parasite hosting , immunology , bacteria , alkyl , organic chemistry , world wide web , computer science , genetics
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(1 H )‐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 IC 50 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 LD 50 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(1 H )‐ones as a potential platform to design potent antileishmanial agents.