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

Authorized Users Only
2017
Authors
Srbljanović, Jelena
Štajner, Tijana
Konstantinović, Jelena M.
Terzić-Jovanović, Nataša
Uzelac, Aleksandra
Bobic, Branko
Šolaja, Bogdan
Djurkovic-Djakovic, Olgica
Article (Published version)
Metadata
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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 >= 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 pr...olonged the survival of treated versus untreated mice, four of which afforded >= 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
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)
Note:
  • The peer-reviewed version: http://cer.ihtm.bg.ac.rs/handle/123456789/3033

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
https://cer.ihtm.bg.ac.rs/handle/123456789/2172
Collections
  • Radovi istraživača / Researchers' publications
Institution/Community
IHTM
TY  - JOUR
AU  - Srbljanović, Jelena
AU  - Štajner, Tijana
AU  - Konstantinović, Jelena M.
AU  - Terzić-Jovanović, Nataša
AU  - Uzelac, Aleksandra
AU  - Bobic, Branko
AU  - Šolaja, Bogdan
AU  - Djurkovic-Djakovic, Olgica
PY  - 2017
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/2172
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 >= 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 >= 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
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
VL  - 50
IS  - 3
SP  - 461
EP  - 466
DO  - 10.1016/j.ijantimicag.2017.06.002
ER  - 
@article{
author = "Srbljanović, Jelena and Štajner, Tijana and Konstantinović, Jelena M. and Terzić-Jovanović, Nataša and Uzelac, Aleksandra and Bobic, Branko and Šolaja, Bogdan and Djurkovic-Djakovic, 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 >= 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 >= 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",
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",
volume = "50",
number = "3",
pages = "461-466",
doi = "10.1016/j.ijantimicag.2017.06.002"
}
Srbljanović, J., Štajner, T., Konstantinović, J. M., Terzić-Jovanović, N., Uzelac, A., Bobic, B., Šolaja, B.,& Djurkovic-Djakovic, 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., 50(3), 461-466.
https://doi.org/10.1016/j.ijantimicag.2017.06.002
Srbljanović J, Štajner T, Konstantinović JM, Terzić-Jovanović N, Uzelac A, Bobic B, Šolaja B, Djurkovic-Djakovic 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 M., Terzić-Jovanović, Nataša, Uzelac, Aleksandra, Bobic, Branko, Šolaja, Bogdan, Djurkovic-Djakovic, 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 . .

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