4-Aminoquinoline-based compounds as antileishmanial agents that inhibit the energy metabolism of Leishmania
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Manzano, Jose IgnacioKonstantinović, Jelena
Scaccabarozzi, Diletta
Perea, Ana
Pavić, Aleksandar
Cavicchini, Loredana
Basilico, Nicoletta
Gamarro, Francisco
Solaja, 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 lt 1 mu M. 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 leishmanicida...l mechanism of this compound. In all, these results support the consideration of compound 1 for the future development of new leishmanicidal drugs.
Keywords:
Mechanism of action / Leishmania / In vitro activity / Drug combination / 4-Aminoquinoline-based compoundsSource:
European Journal of Medicinal Chemistry, 2019, 180, 28-40Publisher:
- Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux
Funding / projects:
- Serbian Academy of Sciences and Arts [F80]
- Ministero dell'Istruzione, dell'Universita 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]
- The synthesis of aminoquinoline-based antimalarials and botulinum neurotoxin A inhibitors (RS-MESTD-Basic Research (BR or ON)-172008)
- Microbial diversity study and characterization of beneficial environmental microorganisms (RS-MESTD-Basic Research (BR or ON)-173048)
DOI: 10.1016/j.ejmech.2019.07.010
ISSN: 0223-5234
PubMed: 31299585
WoS: 000488307100003
Scopus: 2-s2.0-85068511059
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Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Manzano, Jose Ignacio AU - Konstantinović, Jelena AU - Scaccabarozzi, Diletta AU - Perea, Ana AU - Pavić, Aleksandar AU - Cavicchini, Loredana AU - Basilico, Nicoletta AU - Gamarro, Francisco AU - Solaja, Bogdan A. PY - 2019 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/1198 AB - 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 lt 1 mu M. 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. PB - Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux T2 - European Journal of Medicinal Chemistry T1 - 4-Aminoquinoline-based compounds as antileishmanial agents that inhibit the energy metabolism of Leishmania EP - 40 SP - 28 VL - 180 DO - 10.1016/j.ejmech.2019.07.010 ER -
@article{ author = "Manzano, Jose Ignacio and Konstantinović, Jelena and Scaccabarozzi, Diletta and Perea, Ana and Pavić, Aleksandar and Cavicchini, Loredana and Basilico, Nicoletta and Gamarro, Francisco and Solaja, Bogdan A.", year = "2019", 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 lt 1 mu M. 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.", publisher = "Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux", journal = "European Journal of Medicinal Chemistry", title = "4-Aminoquinoline-based compounds as antileishmanial agents that inhibit the energy metabolism of Leishmania", pages = "40-28", volume = "180", doi = "10.1016/j.ejmech.2019.07.010" }
Manzano, J. I., Konstantinović, J., Scaccabarozzi, D., Perea, A., Pavić, A., Cavicchini, L., Basilico, N., Gamarro, F.,& Solaja, B. A.. (2019). 4-Aminoquinoline-based compounds as antileishmanial agents that inhibit the energy metabolism of Leishmania. in European Journal of Medicinal Chemistry Elsevier France-Editions Scientifiques Medicales Elsevier, Issy-Les-Moulineaux., 180, 28-40. https://doi.org/10.1016/j.ejmech.2019.07.010
Manzano JI, Konstantinović J, Scaccabarozzi D, Perea A, Pavić A, Cavicchini L, Basilico N, Gamarro F, Solaja BA. 4-Aminoquinoline-based compounds as antileishmanial agents that inhibit the energy metabolism of Leishmania. in European Journal of Medicinal Chemistry. 2019;180:28-40. doi:10.1016/j.ejmech.2019.07.010 .
Manzano, Jose Ignacio, Konstantinović, Jelena, Scaccabarozzi, Diletta, Perea, Ana, Pavić, Aleksandar, Cavicchini, Loredana, Basilico, Nicoletta, Gamarro, Francisco, Solaja, Bogdan A., "4-Aminoquinoline-based compounds as antileishmanial agents that inhibit the energy metabolism of Leishmania" in European Journal of Medicinal Chemistry, 180 (2019):28-40, https://doi.org/10.1016/j.ejmech.2019.07.010 . .