An aromatic imidazoline derived from chloroquinoline triggers cell cycle arrest and inhibits with high selectivity the Trypanosoma cruzi mammalian host-cells infection.
Trypanosoma cruzi is a hemoflagellated parasite causing Chagas disease, which affects 6-8 million people in the Americas. More than one hundred years after the description of this disease, the available drugs for treating the T. cruzi infection remain largely unsatisfactory. Chloroquinoline and aryl...
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ftdoajarticles:oai:doaj.org/article:0589b3b616b249a98abd20745078f37d 2023-05-15T15:16:55+02:00 An aromatic imidazoline derived from chloroquinoline triggers cell cycle arrest and inhibits with high selectivity the Trypanosoma cruzi mammalian host-cells infection. Roberto I Cuevas-Hernández Richard M B M Girard Luka Krstulović Miroslav Bajić Ariel Mariano Silber 2021-11-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0009994 https://doaj.org/article/0589b3b616b249a98abd20745078f37d EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0009994 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0009994 https://doaj.org/article/0589b3b616b249a98abd20745078f37d PLoS Neglected Tropical Diseases, Vol 15, Iss 11, p e0009994 (2021) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2021 ftdoajarticles https://doi.org/10.1371/journal.pntd.0009994 2023-03-26T01:30:10Z Trypanosoma cruzi is a hemoflagellated parasite causing Chagas disease, which affects 6-8 million people in the Americas. More than one hundred years after the description of this disease, the available drugs for treating the T. cruzi infection remain largely unsatisfactory. Chloroquinoline and arylamidine moieties are separately found in various compounds reported for their anti-trypanosoma activities. In this work we evaluate the anti-T. cruzi activity of a collection of 26 "chimeric" molecules combining choroquinoline and amidine structures. In a first screening using epimastigote forms of the parasite as a proxy for the clinically relevant stages, we selected the compound 7-chloro-4-[4-(4,5-dihydro-1H-imidazol-2-yl)phenoxy]quinoline (named here as A6) that performed better as an anti-T. cruzi compound (IC50 of 2.2 ± 0.3 μM) and showed a low toxicity for the mammalian cell CHO-K1 (CC50 of 137.9 ± 17.3 μM). We initially investigated the mechanism of death associated to the selected compound. The A6 did not trigger phosphatidylserine exposure or plasma membrane permeabilization. Further investigation led us to observe that under short-term incubations (until 6 hours), no alterations of mitochondrial function were observed. However, at longer incubation times (4 days), A6 was able to decrease the intracellular Ca2+, to diminish the intracellular ATP levels, and to collapse mitochondrial inner membrane potential. After analysing the cell cycle, we found as well that A6 produced an arrest in the S phase that impairs the parasite proliferation. Finally, A6 was effective against the infective forms of the parasite during the infection of the mammalian host cells at a nanomolar concentration (IC50(tryps) = 26.7 ± 3.7 nM), exhibiting a selectivity index (SI) of 5,170. Our data suggest that A6 is a promising hit against T. cruzi. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 15 11 e0009994 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Roberto I Cuevas-Hernández Richard M B M Girard Luka Krstulović Miroslav Bajić Ariel Mariano Silber An aromatic imidazoline derived from chloroquinoline triggers cell cycle arrest and inhibits with high selectivity the Trypanosoma cruzi mammalian host-cells infection. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Trypanosoma cruzi is a hemoflagellated parasite causing Chagas disease, which affects 6-8 million people in the Americas. More than one hundred years after the description of this disease, the available drugs for treating the T. cruzi infection remain largely unsatisfactory. Chloroquinoline and arylamidine moieties are separately found in various compounds reported for their anti-trypanosoma activities. In this work we evaluate the anti-T. cruzi activity of a collection of 26 "chimeric" molecules combining choroquinoline and amidine structures. In a first screening using epimastigote forms of the parasite as a proxy for the clinically relevant stages, we selected the compound 7-chloro-4-[4-(4,5-dihydro-1H-imidazol-2-yl)phenoxy]quinoline (named here as A6) that performed better as an anti-T. cruzi compound (IC50 of 2.2 ± 0.3 μM) and showed a low toxicity for the mammalian cell CHO-K1 (CC50 of 137.9 ± 17.3 μM). We initially investigated the mechanism of death associated to the selected compound. The A6 did not trigger phosphatidylserine exposure or plasma membrane permeabilization. Further investigation led us to observe that under short-term incubations (until 6 hours), no alterations of mitochondrial function were observed. However, at longer incubation times (4 days), A6 was able to decrease the intracellular Ca2+, to diminish the intracellular ATP levels, and to collapse mitochondrial inner membrane potential. After analysing the cell cycle, we found as well that A6 produced an arrest in the S phase that impairs the parasite proliferation. Finally, A6 was effective against the infective forms of the parasite during the infection of the mammalian host cells at a nanomolar concentration (IC50(tryps) = 26.7 ± 3.7 nM), exhibiting a selectivity index (SI) of 5,170. Our data suggest that A6 is a promising hit against T. cruzi. |
format |
Article in Journal/Newspaper |
author |
Roberto I Cuevas-Hernández Richard M B M Girard Luka Krstulović Miroslav Bajić Ariel Mariano Silber |
author_facet |
Roberto I Cuevas-Hernández Richard M B M Girard Luka Krstulović Miroslav Bajić Ariel Mariano Silber |
author_sort |
Roberto I Cuevas-Hernández |
title |
An aromatic imidazoline derived from chloroquinoline triggers cell cycle arrest and inhibits with high selectivity the Trypanosoma cruzi mammalian host-cells infection. |
title_short |
An aromatic imidazoline derived from chloroquinoline triggers cell cycle arrest and inhibits with high selectivity the Trypanosoma cruzi mammalian host-cells infection. |
title_full |
An aromatic imidazoline derived from chloroquinoline triggers cell cycle arrest and inhibits with high selectivity the Trypanosoma cruzi mammalian host-cells infection. |
title_fullStr |
An aromatic imidazoline derived from chloroquinoline triggers cell cycle arrest and inhibits with high selectivity the Trypanosoma cruzi mammalian host-cells infection. |
title_full_unstemmed |
An aromatic imidazoline derived from chloroquinoline triggers cell cycle arrest and inhibits with high selectivity the Trypanosoma cruzi mammalian host-cells infection. |
title_sort |
aromatic imidazoline derived from chloroquinoline triggers cell cycle arrest and inhibits with high selectivity the trypanosoma cruzi mammalian host-cells infection. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2021 |
url |
https://doi.org/10.1371/journal.pntd.0009994 https://doaj.org/article/0589b3b616b249a98abd20745078f37d |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 15, Iss 11, p e0009994 (2021) |
op_relation |
https://doi.org/10.1371/journal.pntd.0009994 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0009994 https://doaj.org/article/0589b3b616b249a98abd20745078f37d |
op_doi |
https://doi.org/10.1371/journal.pntd.0009994 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
15 |
container_issue |
11 |
container_start_page |
e0009994 |
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1766347212003999744 |