Examination of the antimalarial potential of experimental aminoquinolines: poor in vitro effect does not preclude in vivo efficacy

2017
Authors
Srbljanović, Jelena
Štajner, Tijana

Konstantinović, Jelena

Terzić-Jovanović, Nataša

Uzelac, Aleksandra

Bobić, Branko

Šolaja, Bogdan

Đurković-Đaković, Olgica

Article (Published version)

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Show full item recordAbstract
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.
Keywords:
Malaria / Aminoquinolines / LDH assay / Thompson test / AdamantaneSource:
International Journal of Antimicrobial Agents, 2017, 50, 3, 461-466Publisher:
- Elsevier Science Bv, Amsterdam
Funding / projects:
- Control of infections by Apicomplexan pathogens: from novel drug targets to prediction (RS-41019)
- The synthesis of aminoquinoline-based antimalarials and botulinum neurotoxin A inhibitors (RS-172008)
DOI: 10.1016/j.ijantimicag.2017.06.002
ISSN: 0924-8579
PubMed: 28668677
WoS: 000408686800025
Scopus: 2-s2.0-85026397158
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Institution/Community
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 . .