Examination of the antimalarial potential of experimental aminoquinolines: poor in vitro effect does not preclude in vivo efficacy
2017
Аутори
Srbljanović, JelenaŠtajner, Tijana
Konstantinović, Jelena
Terzić-Jovanović, Nataša
Uzelac, Aleksandra
Bobić, Branko
Šolaja, Bogdan
Đurković-Đaković, Olgica
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
Malaria remains a major disease in the developing world and globally is the most important parasitic disease causing significant morbidity and mortality. Because of widespread resistance to conventional antimalarials, including chloroquine (CQ), new drugs are urgently needed. Here we report on the antimalarial efficacy, both in vitro and in vivo, of a series of aminoquinoline derivatives with adamantane or benzothiophene as a carrier. In vitro efficacy was evaluated by a lactate dehydrogenase (LDH) assay in cultures of a CQ-sensitive (3D7) and CQ-resistant (Dd2) strain of Plasmodium falcipanim. Of a series of 26 screened compounds, 12 that exerted a growth inhibition rate of gt = 5% were further examined in vitro to determine the 50% inhibitory concentration (IC50) values. Nine compounds shown in preliminary experiments to be non-toxic in vivo were evaluated in C57BL/6 mice infected with Plasmodium herghei ANKA strain using a modified Thompson test. All nine compounds examined in vivo... prolonged the survival of treated versus untreated mice, four of which afforded gt = 60% survival. Most notably, two of these compounds, both with the adamantane carrier, afforded complete cure (100% survival and parasite clearance). Interestingly, one of these compounds had no in vitro effect against the CQ resistant P. falciparum strain. Better in vivo compared with in vitro results suggest a role for compound metabolites rather than the compounds themselves. The results presented here point to adamantane as a carrier that enhances the antimalarial potential of aminoquinolines.
Кључне речи:
Malaria / Aminoquinolines / LDH assay / Thompson test / AdamantaneИзвор:
International Journal of Antimicrobial Agents, 2017, 50, 3, 461-466Издавач:
- Elsevier Science Bv, Amsterdam
Финансирање / пројекти:
- Контрола инфекција апикомплексним патогенима: од нових места деловања лека до предикције (RS-41019)
- Синтеза аминохинолина и њихових деривата као антималарика и инхибитора ботулинум неуротоксина А (RS-172008)
DOI: 10.1016/j.ijantimicag.2017.06.002
ISSN: 0924-8579
PubMed: 28668677
WoS: 000408686800025
Scopus: 2-s2.0-85026397158
Институција/група
Institut za medicinska istraživanjaTY - JOUR AU - Srbljanović, Jelena AU - Štajner, Tijana AU - Konstantinović, Jelena AU - Terzić-Jovanović, Nataša AU - Uzelac, Aleksandra AU - Bobić, Branko AU - Šolaja, Bogdan AU - Đurković-Đaković, Olgica PY - 2017 UR - http://rimi.imi.bg.ac.rs/handle/123456789/757 AB - Malaria remains a major disease in the developing world and globally is the most important parasitic disease causing significant morbidity and mortality. Because of widespread resistance to conventional antimalarials, including chloroquine (CQ), new drugs are urgently needed. Here we report on the antimalarial efficacy, both in vitro and in vivo, of a series of aminoquinoline derivatives with adamantane or benzothiophene as a carrier. In vitro efficacy was evaluated by a lactate dehydrogenase (LDH) assay in cultures of a CQ-sensitive (3D7) and CQ-resistant (Dd2) strain of Plasmodium falcipanim. Of a series of 26 screened compounds, 12 that exerted a growth inhibition rate of gt = 5% were further examined in vitro to determine the 50% inhibitory concentration (IC50) values. Nine compounds shown in preliminary experiments to be non-toxic in vivo were evaluated in C57BL/6 mice infected with Plasmodium herghei ANKA strain using a modified Thompson test. All nine compounds examined in vivo prolonged the survival of treated versus untreated mice, four of which afforded gt = 60% survival. Most notably, two of these compounds, both with the adamantane carrier, afforded complete cure (100% survival and parasite clearance). Interestingly, one of these compounds had no in vitro effect against the CQ resistant P. falciparum strain. Better in vivo compared with in vitro results suggest a role for compound metabolites rather than the compounds themselves. The results presented here point to adamantane as a carrier that enhances the antimalarial potential of aminoquinolines. PB - Elsevier Science Bv, Amsterdam T2 - International Journal of Antimicrobial Agents T1 - Examination of the antimalarial potential of experimental aminoquinolines: poor in vitro effect does not preclude in vivo efficacy EP - 466 IS - 3 SP - 461 VL - 50 DO - 10.1016/j.ijantimicag.2017.06.002 ER -
@article{ author = "Srbljanović, Jelena and Štajner, Tijana and Konstantinović, Jelena and Terzić-Jovanović, Nataša and Uzelac, Aleksandra and Bobić, Branko and Šolaja, Bogdan and Đurković-Đaković, Olgica", year = "2017", abstract = "Malaria remains a major disease in the developing world and globally is the most important parasitic disease causing significant morbidity and mortality. Because of widespread resistance to conventional antimalarials, including chloroquine (CQ), new drugs are urgently needed. Here we report on the antimalarial efficacy, both in vitro and in vivo, of a series of aminoquinoline derivatives with adamantane or benzothiophene as a carrier. In vitro efficacy was evaluated by a lactate dehydrogenase (LDH) assay in cultures of a CQ-sensitive (3D7) and CQ-resistant (Dd2) strain of Plasmodium falcipanim. Of a series of 26 screened compounds, 12 that exerted a growth inhibition rate of gt = 5% were further examined in vitro to determine the 50% inhibitory concentration (IC50) values. Nine compounds shown in preliminary experiments to be non-toxic in vivo were evaluated in C57BL/6 mice infected with Plasmodium herghei ANKA strain using a modified Thompson test. All nine compounds examined in vivo prolonged the survival of treated versus untreated mice, four of which afforded gt = 60% survival. Most notably, two of these compounds, both with the adamantane carrier, afforded complete cure (100% survival and parasite clearance). Interestingly, one of these compounds had no in vitro effect against the CQ resistant P. falciparum strain. Better in vivo compared with in vitro results suggest a role for compound metabolites rather than the compounds themselves. The results presented here point to adamantane as a carrier that enhances the antimalarial potential of aminoquinolines.", publisher = "Elsevier Science Bv, Amsterdam", journal = "International Journal of Antimicrobial Agents", title = "Examination of the antimalarial potential of experimental aminoquinolines: poor in vitro effect does not preclude in vivo efficacy", pages = "466-461", number = "3", volume = "50", doi = "10.1016/j.ijantimicag.2017.06.002" }
Srbljanović, J., Štajner, T., Konstantinović, J., Terzić-Jovanović, N., Uzelac, A., Bobić, B., Šolaja, B.,& Đurković-Đaković, O.. (2017). Examination of the antimalarial potential of experimental aminoquinolines: poor in vitro effect does not preclude in vivo efficacy. in International Journal of Antimicrobial Agents Elsevier Science Bv, Amsterdam., 50(3), 461-466. https://doi.org/10.1016/j.ijantimicag.2017.06.002
Srbljanović J, Štajner T, Konstantinović J, Terzić-Jovanović N, Uzelac A, Bobić B, Šolaja B, Đurković-Đaković O. Examination of the antimalarial potential of experimental aminoquinolines: poor in vitro effect does not preclude in vivo efficacy. in International Journal of Antimicrobial Agents. 2017;50(3):461-466. doi:10.1016/j.ijantimicag.2017.06.002 .
Srbljanović, Jelena, Štajner, Tijana, Konstantinović, Jelena, Terzić-Jovanović, Nataša, Uzelac, Aleksandra, Bobić, Branko, Šolaja, Bogdan, Đurković-Đaković, Olgica, "Examination of the antimalarial potential of experimental aminoquinolines: poor in vitro effect does not preclude in vivo efficacy" in International Journal of Antimicrobial Agents, 50, no. 3 (2017):461-466, https://doi.org/10.1016/j.ijantimicag.2017.06.002 . .