4-Aminoquinoline-based compounds as antileishmanial agents that inhibit the energy metabolism of Leishmania
Само за регистроване кориснике
2019
Аутори
Manzano, Jose IgnacioKonstantinović, Jelena M.
Scaccabarozzi, Diletta
Perea, Ana
Pavić, Aleksandar
Cavicchini, Loredana
Basilico, Nicoletta
Gamarro, Francisco
Šolaja, Bogdan A.
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
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.
Кључне речи:
4-Aminoquinoline-based compounds / Drug combination / In vitro activity / Leishmania / Mechanism of actionИзвор:
European Journal of Medicinal Chemistry, 2019, 180, 28-40Издавач:
- Elsevier
Финансирање / пројекти:
- Синтеза аминохинолина и њихових деривата као антималарика и инхибитора ботулинум неуротоксина А (RS-MESTD-Basic Research (BR or ON)-172008)
- Изучавање микробиолошког диверзитета и карактеризација корисних срединских микроорганизама (RS-MESTD-Basic Research (BR or ON)-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).
Напомена:
- Supplementary material: http://cherry.chem.bg.ac.rs/handle/123456789/3288
DOI: 10.1016/j.ejmech.2019.07.010
ISSN: 0223-5234
WoS: 000488307100003
Scopus: 2-s2.0-85068511059
Колекције
Институција/група
Hemijski fakultet / Faculty of ChemistryTY - JOUR AU - Manzano, Jose Ignacio AU - Konstantinović, Jelena M. AU - Scaccabarozzi, Diletta AU - Perea, Ana AU - Pavić, Aleksandar AU - Cavicchini, Loredana AU - Basilico, Nicoletta AU - Gamarro, Francisco AU - Šolaja, Bogdan A. PY - 2019 UR - https://cherry.chem.bg.ac.rs/handle/123456789/3287 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 < 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 mechanism of this compound. In all, these results support the consideration of compound 1 for the future development of new leishmanicidal drugs. PB - Elsevier T2 - European Journal of Medicinal Chemistry T1 - 4-Aminoquinoline-based compounds as antileishmanial agents that inhibit the energy metabolism of Leishmania VL - 180 SP - 28 EP - 40 DO - 10.1016/j.ejmech.2019.07.010 ER -
@article{ author = "Manzano, Jose Ignacio and Konstantinović, Jelena M. and Scaccabarozzi, Diletta and Perea, Ana and Pavić, Aleksandar and Cavicchini, Loredana and Basilico, Nicoletta and Gamarro, Francisco and Šolaja, 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 < 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 mechanism of this compound. In all, these results support the consideration of compound 1 for the future development of new leishmanicidal drugs.", publisher = "Elsevier", journal = "European Journal of Medicinal Chemistry", title = "4-Aminoquinoline-based compounds as antileishmanial agents that inhibit the energy metabolism of Leishmania", volume = "180", pages = "28-40", doi = "10.1016/j.ejmech.2019.07.010" }
Manzano, J. I., Konstantinović, J. M., Scaccabarozzi, D., Perea, A., Pavić, A., Cavicchini, L., Basilico, N., Gamarro, F.,& Šolaja, B. A.. (2019). 4-Aminoquinoline-based compounds as antileishmanial agents that inhibit the energy metabolism of Leishmania. in European Journal of Medicinal Chemistry Elsevier., 180, 28-40. https://doi.org/10.1016/j.ejmech.2019.07.010
Manzano JI, Konstantinović JM, Scaccabarozzi D, Perea A, Pavić A, Cavicchini L, Basilico N, Gamarro F, Šolaja 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 M., Scaccabarozzi, Diletta, Perea, Ana, Pavić, Aleksandar, Cavicchini, Loredana, Basilico, Nicoletta, Gamarro, Francisco, Šolaja, 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 . .