Structure–activity relationships in a series of antiplasmodial thieno[2,3-b]pyridines
Abstract Background Malaria is one of the most prevalent tropical infectious diseases. Since recently cases of artemisinin resistance were reported, novel anti-malarial drugs are required which differ from artemisinins in structure and biological target. The plasmodial glycogen synthase kinase-3 (Pf...
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ftdoajarticles:oai:doaj.org/article:86bec5b15da04074875dc25fedb8b09d 2023-05-15T15:15:26+02:00 Structure–activity relationships in a series of antiplasmodial thieno[2,3-b]pyridines Andreas Masch Abed Nasereddin Arne Alder Megan J. Bird Sandra I. Schweda Lutz Preu Christian Doerig Ron Dzikowski Tim W. Gilberger Conrad Kunick 2019-03-01T00:00:00Z https://doi.org/10.1186/s12936-019-2725-y https://doaj.org/article/86bec5b15da04074875dc25fedb8b09d EN eng BMC http://link.springer.com/article/10.1186/s12936-019-2725-y https://doaj.org/toc/1475-2875 doi:10.1186/s12936-019-2725-y 1475-2875 https://doaj.org/article/86bec5b15da04074875dc25fedb8b09d Malaria Journal, Vol 18, Iss 1, Pp 1-10 (2019) Anti-malarial drugs Atropisomers Axial chirality Drug discovery Malaria PfGSK-3 Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 article 2019 ftdoajarticles https://doi.org/10.1186/s12936-019-2725-y 2022-12-30T21:04:54Z Abstract Background Malaria is one of the most prevalent tropical infectious diseases. Since recently cases of artemisinin resistance were reported, novel anti-malarial drugs are required which differ from artemisinins in structure and biological target. The plasmodial glycogen synthase kinase-3 (PfGSK-3) was suggested as a new anti-malarial drug target. 4-Phenylthieno[2,3-b]pyridines were previously identified as selective PfGSK-3 inhibitors with antiplasmodial activity. The present study aims at identifying a molecular position on this scaffold for the attachment of side chains in order to improve solubility and antiplasmodial activity. Furthermore, the role of axial chirality in the compound class for antiplasmodial activity and PfGSK-3 inhibition was investigated. Methods 4-Phenylthieno[2,3-b]pyridines with substituents in 4-position of the phenyl ring were docked into the ATP binding site of PfGSK-3. The compounds were synthesized employing a Thorpe reaction as final step. The enantiomers of one congener were separated by chiral HPLC. All derivatives were tested for inhibition of asexual erythrocytic stages of transgenic NF54-luc Plasmodium falciparum. Selected compounds with promising antiplasmodial activity were further evaluated for inhibition of HEK293 cells as well as inhibition of isolated PfGSK-3 and HsGSK-3. The kinetic aqueous solubility was assessed by laser nephelometry. Results The para position at the 4-phenyl ring of the title compounds was identified as a suitable point for the attachment of side chains. While alkoxy substituents in this position led to decreased antiplasmodial activity, alkylamino groups retained antiparasitic potency. The most promising of these congeners (4h) was investigated in detail. This compound is a selective PfGSK-3 inhibitor (versus the human GSK-3 orthologue), and exhibits improved antiplasmodial activity in vitro as well as better solubility in aqueous media than its unsubstituted parent structure. The derivative 4b was separated into the atropisomers, and it was ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Malaria Journal 18 1 |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
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topic |
Anti-malarial drugs Atropisomers Axial chirality Drug discovery Malaria PfGSK-3 Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
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Anti-malarial drugs Atropisomers Axial chirality Drug discovery Malaria PfGSK-3 Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 Andreas Masch Abed Nasereddin Arne Alder Megan J. Bird Sandra I. Schweda Lutz Preu Christian Doerig Ron Dzikowski Tim W. Gilberger Conrad Kunick Structure–activity relationships in a series of antiplasmodial thieno[2,3-b]pyridines |
topic_facet |
Anti-malarial drugs Atropisomers Axial chirality Drug discovery Malaria PfGSK-3 Arctic medicine. Tropical medicine RC955-962 Infectious and parasitic diseases RC109-216 |
description |
Abstract Background Malaria is one of the most prevalent tropical infectious diseases. Since recently cases of artemisinin resistance were reported, novel anti-malarial drugs are required which differ from artemisinins in structure and biological target. The plasmodial glycogen synthase kinase-3 (PfGSK-3) was suggested as a new anti-malarial drug target. 4-Phenylthieno[2,3-b]pyridines were previously identified as selective PfGSK-3 inhibitors with antiplasmodial activity. The present study aims at identifying a molecular position on this scaffold for the attachment of side chains in order to improve solubility and antiplasmodial activity. Furthermore, the role of axial chirality in the compound class for antiplasmodial activity and PfGSK-3 inhibition was investigated. Methods 4-Phenylthieno[2,3-b]pyridines with substituents in 4-position of the phenyl ring were docked into the ATP binding site of PfGSK-3. The compounds were synthesized employing a Thorpe reaction as final step. The enantiomers of one congener were separated by chiral HPLC. All derivatives were tested for inhibition of asexual erythrocytic stages of transgenic NF54-luc Plasmodium falciparum. Selected compounds with promising antiplasmodial activity were further evaluated for inhibition of HEK293 cells as well as inhibition of isolated PfGSK-3 and HsGSK-3. The kinetic aqueous solubility was assessed by laser nephelometry. Results The para position at the 4-phenyl ring of the title compounds was identified as a suitable point for the attachment of side chains. While alkoxy substituents in this position led to decreased antiplasmodial activity, alkylamino groups retained antiparasitic potency. The most promising of these congeners (4h) was investigated in detail. This compound is a selective PfGSK-3 inhibitor (versus the human GSK-3 orthologue), and exhibits improved antiplasmodial activity in vitro as well as better solubility in aqueous media than its unsubstituted parent structure. The derivative 4b was separated into the atropisomers, and it was ... |
format |
Article in Journal/Newspaper |
author |
Andreas Masch Abed Nasereddin Arne Alder Megan J. Bird Sandra I. Schweda Lutz Preu Christian Doerig Ron Dzikowski Tim W. Gilberger Conrad Kunick |
author_facet |
Andreas Masch Abed Nasereddin Arne Alder Megan J. Bird Sandra I. Schweda Lutz Preu Christian Doerig Ron Dzikowski Tim W. Gilberger Conrad Kunick |
author_sort |
Andreas Masch |
title |
Structure–activity relationships in a series of antiplasmodial thieno[2,3-b]pyridines |
title_short |
Structure–activity relationships in a series of antiplasmodial thieno[2,3-b]pyridines |
title_full |
Structure–activity relationships in a series of antiplasmodial thieno[2,3-b]pyridines |
title_fullStr |
Structure–activity relationships in a series of antiplasmodial thieno[2,3-b]pyridines |
title_full_unstemmed |
Structure–activity relationships in a series of antiplasmodial thieno[2,3-b]pyridines |
title_sort |
structure–activity relationships in a series of antiplasmodial thieno[2,3-b]pyridines |
publisher |
BMC |
publishDate |
2019 |
url |
https://doi.org/10.1186/s12936-019-2725-y https://doaj.org/article/86bec5b15da04074875dc25fedb8b09d |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Malaria Journal, Vol 18, Iss 1, Pp 1-10 (2019) |
op_relation |
http://link.springer.com/article/10.1186/s12936-019-2725-y https://doaj.org/toc/1475-2875 doi:10.1186/s12936-019-2725-y 1475-2875 https://doaj.org/article/86bec5b15da04074875dc25fedb8b09d |
op_doi |
https://doi.org/10.1186/s12936-019-2725-y |
container_title |
Malaria Journal |
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18 |
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1 |
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1766345794185592832 |