2. Academic Validation
  3. 4-Aminoquinoline-based compounds as antileishmanial agents that inhibit the energy metabolism of Leishmania

4-Aminoquinoline-based compounds as antileishmanial agents that inhibit the energy metabolism of Leishmania

  • Eur J Med Chem. 2019 Oct 15:180:28-40. doi: 10.1016/j.ejmech.2019.07.010.
José Ignacio Manzano 1,  Jelena Konstantinović 2,  Diletta Scaccabarozzi 3,  Ana Perea 1,  Aleksandar Pavić 4,  Loredana Cavicchini 3,  Nicoletta Basilico 3,  Francisco Gamarro 1,  Bogdan A Šolaja 5
Affiliations

Affiliations

  • 1 Instituto de Parasitología y Biomedicina "López-Neyra", IPBLN-CSIC, Parque Tecnológico de Ciencias de la Salud, Avda. del Conocimiento s/n, 18016, Granada, Spain.
  • 2 University of Belgrade, Faculty of Chemistry, Studentski trg 16, P.O. Box 51, 11158, Belgrade, Serbia.
  • 3 Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università degli Studi di Milano, Via Pascal, 36, 20133, Milan, Italy.
  • 4 Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.
  • 5 University of Belgrade, Faculty of Chemistry, Studentski trg 16, P.O. Box 51, 11158, Belgrade, Serbia; Serbian Academy of Science and Arts, Knez Mihailova 35, 11158, Belgrade, Serbia. Electronic address: [email protected].
PMID: 31299585 DOI: 10.1016/j.ejmech.2019.07.010
Abstract

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.

Keywords

4-Aminoquinoline-based compounds; Drug combination; In vitro activity; Leishmania; Mechanism of action.

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