Theoretical and Experimental Study of New Dihydroorotate Dehydrogenase and Tryparedoxin Peroxidase Inhibitors: One More Step in the Study of Leishmaniasis Infection

Abstract

In this study, the viability of new dihydroorotate dehydrogenase and tryparedoxin peroxidase inhibitors is reported. In vitro antileishmanial activity was evaluated using a Leishmania (V) panamensis strain, and the cytotoxicity of the compounds was assessed using U-937 cells. The in vivo therapeutic response was evaluated in golden hamsters (Mesocricetus auratus) experimentally infected with L. (V) panamensis and treated with a 1% topical formulation of compounds 4a–f. On the other hand, in silico studies considering the synthesized compounds were also carried out. All of the compounds showed promising in vitro activity, with mean EC50 effective concentration values ​​ranging from 3.8 µM to 19.3 µM. Likewise, treatment with compounds 4a–f produced improvement in most of the hamsters and cured some; in particular, those treated with compounds 4b, 4c, 4d, and 4f reacted the best. Molecular dynamics (MD) simulations, computational docking, and MM/GBSA studies indicate the promising bioavailability and absorption characteristics of the studied compounds, which are expected to be orally active. In addition, the studied 2-arylquinolines are absorbable at the blood–brain barrier, but not in the gastrointestinal tract. Finally, ADMET properties suggest that these molecules can be safely used as leishmaniasis inhibitors.