Novel conjugated quinoline-indoles compromise Plasmodium falciparum mitochondrial function and show promising antimalarial activity

Silvia Teguh, Nectarios Klonis, Sandra Duffy, Leonardo Lucantoni, Vicky M Avery, Craig Anthony Hutton, Jonathan Bayldon Baell, Leann Tilley

Research output: Contribution to journalArticleResearchpeer-review

Abstract

A novel class of antimalarial compounds, based on an indol-3-yl linked to the 2-position of a 4-aminoquinoline moiety, shows promising activity against the malaria parasite, Plasmodium falciparum. Compounds with a quaternary nitrogen on the quinoline show improved activity against the chloroquine-resistant K1 strain. Nonquaternerized 4-amino-quinolines retain significant potency but are relatively less active against the K1 strain. Alkylation of the 4-amino group preferentially improves the activity against the chloroquine-sensitive 3D7 strain. The quinoline-indoles show only weak activity as inhibitors of beta-hematin formation, and their activities are only weakly antagonized by a hemoglobinase inhibitor. The compounds appear to dissipate mitochondrial potential as an early event in their antimalarial action and therefore may exert their activity by compromising Plasmodium mitochondrial function. Interestingly, we observed a structural relationship between our compounds and the anticancer and anthelminthic compound, pyrvinium pamoate, which has also been proposed to exert its action via compromising mitochondrial function.
Original languageEnglish
Pages (from-to)6200 - 6215
Number of pages16
JournalJournal of Medicinal Chemistry
Volume56
Issue number15
DOIs
Publication statusPublished - 2013

Cite this

Teguh, Silvia ; Klonis, Nectarios ; Duffy, Sandra ; Lucantoni, Leonardo ; Avery, Vicky M ; Hutton, Craig Anthony ; Baell, Jonathan Bayldon ; Tilley, Leann. / Novel conjugated quinoline-indoles compromise Plasmodium falciparum mitochondrial function and show promising antimalarial activity. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 15. pp. 6200 - 6215.
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abstract = "A novel class of antimalarial compounds, based on an indol-3-yl linked to the 2-position of a 4-aminoquinoline moiety, shows promising activity against the malaria parasite, Plasmodium falciparum. Compounds with a quaternary nitrogen on the quinoline show improved activity against the chloroquine-resistant K1 strain. Nonquaternerized 4-amino-quinolines retain significant potency but are relatively less active against the K1 strain. Alkylation of the 4-amino group preferentially improves the activity against the chloroquine-sensitive 3D7 strain. The quinoline-indoles show only weak activity as inhibitors of beta-hematin formation, and their activities are only weakly antagonized by a hemoglobinase inhibitor. The compounds appear to dissipate mitochondrial potential as an early event in their antimalarial action and therefore may exert their activity by compromising Plasmodium mitochondrial function. Interestingly, we observed a structural relationship between our compounds and the anticancer and anthelminthic compound, pyrvinium pamoate, which has also been proposed to exert its action via compromising mitochondrial function.",
author = "Silvia Teguh and Nectarios Klonis and Sandra Duffy and Leonardo Lucantoni and Avery, {Vicky M} and Hutton, {Craig Anthony} and Baell, {Jonathan Bayldon} and Leann Tilley",
year = "2013",
doi = "10.1021/jm400656s",
language = "English",
volume = "56",
pages = "6200 -- 6215",
journal = "Journal of Medicinal Chemistry",
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Novel conjugated quinoline-indoles compromise Plasmodium falciparum mitochondrial function and show promising antimalarial activity. / Teguh, Silvia; Klonis, Nectarios; Duffy, Sandra; Lucantoni, Leonardo; Avery, Vicky M; Hutton, Craig Anthony; Baell, Jonathan Bayldon; Tilley, Leann.

In: Journal of Medicinal Chemistry, Vol. 56, No. 15, 2013, p. 6200 - 6215.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Klonis, Nectarios

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AB - A novel class of antimalarial compounds, based on an indol-3-yl linked to the 2-position of a 4-aminoquinoline moiety, shows promising activity against the malaria parasite, Plasmodium falciparum. Compounds with a quaternary nitrogen on the quinoline show improved activity against the chloroquine-resistant K1 strain. Nonquaternerized 4-amino-quinolines retain significant potency but are relatively less active against the K1 strain. Alkylation of the 4-amino group preferentially improves the activity against the chloroquine-sensitive 3D7 strain. The quinoline-indoles show only weak activity as inhibitors of beta-hematin formation, and their activities are only weakly antagonized by a hemoglobinase inhibitor. The compounds appear to dissipate mitochondrial potential as an early event in their antimalarial action and therefore may exert their activity by compromising Plasmodium mitochondrial function. Interestingly, we observed a structural relationship between our compounds and the anticancer and anthelminthic compound, pyrvinium pamoate, which has also been proposed to exert its action via compromising mitochondrial function.

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