Aminoquinolines afford resistance to cerebral malaria in susceptible mice
Authors
Srbljanović, Jelena
Bobić, Branko
Štajner, Tijana

Uzelac, Aleksandra

Opsenica, Igor

Terzić-Jovanović, Nataša

Bauman, Neda

Šolaja, Bogdan

Đurković-Đaković, Olgica

Article (Published version)
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Objectives: Malaria treatment is impeded by increasing resistance to conventional antimalarial drugs. Here we explored the activity of ten novel benzothiophene, thiophene and benzene aminoquinolines. Methods: In vitro testing was performed by the lactate dehydrogenase assay in chloroquine (CQ)-sensitive Plasmodium falciparum strain 3D7 and CQ-resistant (CQR) P. falciparum strain Dd2. In vivo activity was evaluated by a modified Thompson test using C57BL/6 mice infected with Plasmodium berghei ANKA strain. Results: Nine of the ten compounds had a lower 50% inhibitory concentration (IC50) than CQ against the CQR strain Dd2. Five of these compounds that were available for in vivo evaluation were shown to be non-toxic. All five compounds administered at a dose of 160 mg/kg/day for 3 days prolonged the survival of treated compared with untreated mice. Untreated control mice died by Day 7 with a mean parasitaemia of 15%. Among treated mice, a dichotomous outcome was observed, with a two-thir...d majority of treated mice dying by Day 17 with a low mean parasitaemia of 5%, whilst one-third survived longer with a mean hyperparasitaemia of 70%; specifically, five of these mice survived a mean of 25 days, whilst two even survived past Day 31. Conclusions: The significant antimalarial potential of this aminoquinoline series is illustrated by its excellent in vitro activity against the CQR P. falciparum strain and significant in vivo activity. Interestingly, compounds ClAQ7, ClAQ9 and ClAQ11 were able to confer resistance to cerebral malaria and afford a switch to hyperparasitaemia to mice prone to the neurological syndrome.
Keywords:
Malaria / Aminoquinolines / Plasmodium berghei / C57BL/6 mice / HyperparasitaemiaSource:
Journal of Global Antimicrobial Resistance, 2020, 23, 20-25Publisher:
- 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)
DOI: 10.1016/j.jgar.2020.07.027
ISSN: 2213-7165
PubMed: 32810640
WoS: 000604981100005
Scopus: 2-s2.0-85090019754
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IHTMTY - JOUR AU - Srbljanović, Jelena AU - Bobić, Branko AU - Štajner, Tijana AU - Uzelac, Aleksandra AU - Opsenica, Igor AU - Terzić-Jovanović, Nataša AU - Bauman, Neda AU - Šolaja, Bogdan AU - Đurković-Đaković, Olgica PY - 2020 UR - https://cer.ihtm.bg.ac.rs/handle/123456789/3721 AB - Objectives: Malaria treatment is impeded by increasing resistance to conventional antimalarial drugs. Here we explored the activity of ten novel benzothiophene, thiophene and benzene aminoquinolines. Methods: In vitro testing was performed by the lactate dehydrogenase assay in chloroquine (CQ)-sensitive Plasmodium falciparum strain 3D7 and CQ-resistant (CQR) P. falciparum strain Dd2. In vivo activity was evaluated by a modified Thompson test using C57BL/6 mice infected with Plasmodium berghei ANKA strain. Results: Nine of the ten compounds had a lower 50% inhibitory concentration (IC50) than CQ against the CQR strain Dd2. Five of these compounds that were available for in vivo evaluation were shown to be non-toxic. All five compounds administered at a dose of 160 mg/kg/day for 3 days prolonged the survival of treated compared with untreated mice. Untreated control mice died by Day 7 with a mean parasitaemia of 15%. Among treated mice, a dichotomous outcome was observed, with a two-third majority of treated mice dying by Day 17 with a low mean parasitaemia of 5%, whilst one-third survived longer with a mean hyperparasitaemia of 70%; specifically, five of these mice survived a mean of 25 days, whilst two even survived past Day 31. Conclusions: The significant antimalarial potential of this aminoquinoline series is illustrated by its excellent in vitro activity against the CQR P. falciparum strain and significant in vivo activity. Interestingly, compounds ClAQ7, ClAQ9 and ClAQ11 were able to confer resistance to cerebral malaria and afford a switch to hyperparasitaemia to mice prone to the neurological syndrome. PB - Elsevier T2 - Journal of Global Antimicrobial Resistance T1 - Aminoquinolines afford resistance to cerebral malaria in susceptible mice VL - 23 SP - 20 EP - 25 DO - 10.1016/j.jgar.2020.07.027 ER -
@article{ author = "Srbljanović, Jelena and Bobić, Branko and Štajner, Tijana and Uzelac, Aleksandra and Opsenica, Igor and Terzić-Jovanović, Nataša and Bauman, Neda and Šolaja, Bogdan and Đurković-Đaković, Olgica", year = "2020", abstract = "Objectives: Malaria treatment is impeded by increasing resistance to conventional antimalarial drugs. Here we explored the activity of ten novel benzothiophene, thiophene and benzene aminoquinolines. Methods: In vitro testing was performed by the lactate dehydrogenase assay in chloroquine (CQ)-sensitive Plasmodium falciparum strain 3D7 and CQ-resistant (CQR) P. falciparum strain Dd2. In vivo activity was evaluated by a modified Thompson test using C57BL/6 mice infected with Plasmodium berghei ANKA strain. Results: Nine of the ten compounds had a lower 50% inhibitory concentration (IC50) than CQ against the CQR strain Dd2. Five of these compounds that were available for in vivo evaluation were shown to be non-toxic. All five compounds administered at a dose of 160 mg/kg/day for 3 days prolonged the survival of treated compared with untreated mice. Untreated control mice died by Day 7 with a mean parasitaemia of 15%. Among treated mice, a dichotomous outcome was observed, with a two-third majority of treated mice dying by Day 17 with a low mean parasitaemia of 5%, whilst one-third survived longer with a mean hyperparasitaemia of 70%; specifically, five of these mice survived a mean of 25 days, whilst two even survived past Day 31. Conclusions: The significant antimalarial potential of this aminoquinoline series is illustrated by its excellent in vitro activity against the CQR P. falciparum strain and significant in vivo activity. Interestingly, compounds ClAQ7, ClAQ9 and ClAQ11 were able to confer resistance to cerebral malaria and afford a switch to hyperparasitaemia to mice prone to the neurological syndrome.", publisher = "Elsevier", journal = "Journal of Global Antimicrobial Resistance", title = "Aminoquinolines afford resistance to cerebral malaria in susceptible mice", volume = "23", pages = "20-25", doi = "10.1016/j.jgar.2020.07.027" }
Srbljanović, J., Bobić, B., Štajner, T., Uzelac, A., Opsenica, I., Terzić-Jovanović, N., Bauman, N., Šolaja, B.,& Đurković-Đaković, O.. (2020). Aminoquinolines afford resistance to cerebral malaria in susceptible mice. in Journal of Global Antimicrobial Resistance Elsevier., 23, 20-25. https://doi.org/10.1016/j.jgar.2020.07.027
Srbljanović J, Bobić B, Štajner T, Uzelac A, Opsenica I, Terzić-Jovanović N, Bauman N, Šolaja B, Đurković-Đaković O. Aminoquinolines afford resistance to cerebral malaria in susceptible mice. in Journal of Global Antimicrobial Resistance. 2020;23:20-25. doi:10.1016/j.jgar.2020.07.027 .
Srbljanović, Jelena, Bobić, Branko, Štajner, Tijana, Uzelac, Aleksandra, Opsenica, Igor, Terzić-Jovanović, Nataša, Bauman, Neda, Šolaja, Bogdan, Đurković-Đaković, Olgica, "Aminoquinolines afford resistance to cerebral malaria in susceptible mice" in Journal of Global Antimicrobial Resistance, 23 (2020):20-25, https://doi.org/10.1016/j.jgar.2020.07.027 . .