Synthesis, anti-parasitic activity and QSAR study of a new library of polysubstituted tetrahydronaphtho[1,2-b]azepines

Abstract

A new series of twenty two 2-exo-aryl(heteroaryl)-1,4-epoxytetrahydronaphtho[1,2-b]azepines 8–10 and eighteen cis-2-aryl(heteroaryl)-4-hydroxytetrahydronaphtho[1,2-b]azepines 11–13 were synthesized, and most of them were tested for their ability to inhibit the in vitro growth of the extracellular forms of Trypanosoma cruzi and Leishmania infantum parasites. Cell toxicity was also determined on Vero and THP-1 mammalian cells. Seventeen compounds exhibited potent activity against the epimastigotes (IC50 lower than 20 µM), without cytotoxicity on Vero cells. Ten compounds also showed remarkable anti-leishmanial properties against the promastigote form of the parasite (IC50 lower than 20 µM), but most of them were found cytotoxic for HTP-1 cells. We have also performed a quantitative structure activity relationship analysis by means of the multivariate lineal regression (MLR) technique with a family of ninety-four tetrahydro-1-benzazepine and tetrahydronaphtho[1,2-b]azepine derivatives with anti-parasitic activity. The aim of this study is to develop a tool that permits us to elucidate the structural features, which influence in the bioactivity of these compounds. The QSAR prediction models for Trypanosoma cruzi and Leishmania infantum were acceptable with a correlation coefficient values (R) of 0.668 and 0.852, respectively, in the prediction of those activities.