Among neglected tropical diseases, leishmaniasis is one of the most relevant with an estimated 30,000 deaths annually. Existing therapies have serious drawbacks in safety, drug resistance, field-adapted application and cost; therefore, new safer and shorter treatments are needed for this disease. Here we report on the synthesis of novel 4-amino-7-chloroquinoline-based compounds with leishmanicidal activity, together with deeper insight into the mechanism of action of our previously published hit compound 1. New derivatives showed comparable activity to 1 against both promastigote and intracellular amastigote forms of Leishmania infantum, with IC50 < 1 μM. Furthermore, we have determined that compound 1 induced a decrease of intracellular ATP levels, as well as a mitochondrial depolarization, together with an alteration of plasma membrane permeability and a significant ROS production. The inhibition of the energy metabolism of Leishmania plays an important role in the leishmanicidal mechanism of this compound. In all, these results support the consideration of compound 1 for the future development of new leishmanicidal drugs.
4-Aminoquinoline-based compounds as antileishmanial agents that inhibit the energy metabolism of Leishmania / J.I. Manzano, J. Konstantinovic, D. Scaccabarozzi, A. Perea, A. Pavic, L. Cavicchini, N. Basilico, F. Gamarro, B.A. Solaja. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - 180(2019 Oct 15), pp. 28-40.
|Titolo:||4-Aminoquinoline-based compounds as antileishmanial agents that inhibit the energy metabolism of Leishmania|
BASILICO, NICOLETTA (Corresponding)
|Parole Chiave:||4-Aminoquinoline-based compounds; Drug combination; In vitro activity; Leishmania; Mechanism of action|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Progetto:||Towards multi-stage drugs to fight poverty related and neglected parasitic diseases: synthetic and natural compounds directed against Leishmania, Plasmodium and Schistosoma life stages and assessment of their mechanisms of action.|
|Data di pubblicazione:||15-ott-2019|
|Data ahead of print / Data di stampa:||5-lug-2019|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.ejmech.2019.07.010|
|Appare nelle tipologie:||01 - Articolo su periodico|