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

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2017
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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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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.

Keywords:
Malaria / Aminoquinolines / LDH assay / Thompson test / Adamantane
Source:
International Journal of Antimicrobial Agents, 2017, 50, 3, 461-466
Publisher:
  • 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
[ Google Scholar ]
3
3
URI
http://rimi.imi.bg.ac.rs/handle/123456789/757
Collections
  • Radovi istraživača / Researchers' publications
Institution/Community
Institut za medicinska istraživanja
TY  - 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
UR  - conv_4106
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",
url = "conv_4106"
}
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
conv_4106
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
conv_4106 .
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 .,
conv_4106 .

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