4-Aminoquinoline-based compounds as antileishmanial agents that inhibit the energy metabolism of Leishmania
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AuthorsManzano, Jose Ignacio
Šolaja, Bogdan A.
Article (Published version)
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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 mM. 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 mec...hanism 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
Source:European Journal of Medicinal Chemistry, 2019, 180, 28-40
- The synthesis of aminoquinoline-based antimalarials and botulinum neurotoxin A inhibitors (RS-172008)
- Microbial diversity study and characterization of beneficial environmental microorganisms (RS-173048)
- Serbian Academy of Sciences and Arts (BS, Grant F80)
- Ministero dell’Istruzione, dell’Universit a e della Ricerca [PRIN 2015.4JRJPP_004]
- University of Milan “Piano sostegno alla Ricerca, Linea 2 2018"
- Spanish Ministerio de Ciencia, Innovacion y Universidades Grant (RTI2018-097210-B-I00 to FG).
- Supplementary material: http://cherry.chem.bg.ac.rs/handle/123456789/3288