Antiplasmodial dihetarylthioethers target the coenzyme A synthesis pathway in Plasmodium falciparum erythrocytic stages
Abstract Background Malaria is a widespread infectious disease that threatens a large proportion of the population in tropical and subtropical areas. Given the emerging resistance against the current standard anti-malaria chemotherapeutics, the development of alternative drugs is urgently needed. Ne...
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doaj-79a2987d18ef42f5ae8eb0b74cbb52b52020-11-25T01:51:43ZengBMCMalaria Journal1475-28752017-05-0116111010.1186/s12936-017-1839-3Antiplasmodial dihetarylthioethers target the coenzyme A synthesis pathway in Plasmodium falciparum erythrocytic stagesThomas Weidner0Leonardo Lucantoni1Abed Nasereddin2Lutz Preu3Peter G. Jones4Ron Dzikowski5Vicky M. Avery6Conrad Kunick7Institut für Medizinische und Pharmazeutische Chemie, Technische Universität BraunschweigDiscovery Biology, Griffith Institute for Drug Discovery, Griffith UniversityDepartment of Microbiology and Molecular Genetics, IMRIC, The Kuvin Center for the Study of Infectious and Tropical Diseases, The Hebrew University-Hadassah Medical SchoolInstitut für Medizinische und Pharmazeutische Chemie, Technische Universität BraunschweigInstitut für Anorganische und Analytische Chemie, Technische Universität BraunschweigDepartment of Microbiology and Molecular Genetics, IMRIC, The Kuvin Center for the Study of Infectious and Tropical Diseases, The Hebrew University-Hadassah Medical SchoolDiscovery Biology, Griffith Institute for Drug Discovery, Griffith UniversityInstitut für Medizinische und Pharmazeutische Chemie, Technische Universität BraunschweigAbstract Background Malaria is a widespread infectious disease that threatens a large proportion of the population in tropical and subtropical areas. Given the emerging resistance against the current standard anti-malaria chemotherapeutics, the development of alternative drugs is urgently needed. New anti-malarials representing chemotypes unrelated to currently used drugs have an increased potential for displaying novel mechanisms of action and thus exhibit low risk of cross-resistance against established drugs. Results Phenotypic screening of a small library (32 kinase-inhibitor analogs) against Plasmodium falciparum NF54-luc asexual erythrocytic stage parasites identified a diarylthioether structurally unrelated to registered drugs. Hit expansion led to a series in which the most potent congener displayed nanomolar antiparasitic activity (IC50 = 39 nM, 3D7 strain). Structure–activity relationship analysis revealed a thieno[2,3-d]pyrimidine on one side of the thioether linkage as a prerequisite for antiplasmodial activity. Within the series, the oxazole derivative KuWei173 showed high potency (IC50 = 75 nM; 3D7 strain), good solubility in aqueous solvents (1.33 mM), and >100-fold selectivity toward human cell lines. Rescue experiments identified inhibition of the plasmodial coenzyme A synthesis as a possible mode of action for this compound class. Conclusions The class of antiplasmodial bishetarylthioethers reported here has been shown to interfere with plasmodial coenzyme A synthesis, a mechanism of action not yet exploited for registered anti-malarial drugs. The oxazole congener KuWei173 displays double-digit nanomolar antiplasmodial activity, selectivity against human cell lines, high drug likeness, and thus represents a promising chemical starting point for further drug development.http://link.springer.com/article/10.1186/s12936-017-1839-3Anti-malaria drugsCoenzyme A synthesisDrug discoveryMalaria1,3,4-OxadiazoleOxazole |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Thomas Weidner Leonardo Lucantoni Abed Nasereddin Lutz Preu Peter G. Jones Ron Dzikowski Vicky M. Avery Conrad Kunick |
spellingShingle |
Thomas Weidner Leonardo Lucantoni Abed Nasereddin Lutz Preu Peter G. Jones Ron Dzikowski Vicky M. Avery Conrad Kunick Antiplasmodial dihetarylthioethers target the coenzyme A synthesis pathway in Plasmodium falciparum erythrocytic stages Malaria Journal Anti-malaria drugs Coenzyme A synthesis Drug discovery Malaria 1,3,4-Oxadiazole Oxazole |
author_facet |
Thomas Weidner Leonardo Lucantoni Abed Nasereddin Lutz Preu Peter G. Jones Ron Dzikowski Vicky M. Avery Conrad Kunick |
author_sort |
Thomas Weidner |
title |
Antiplasmodial dihetarylthioethers target the coenzyme A synthesis pathway in Plasmodium falciparum erythrocytic stages |
title_short |
Antiplasmodial dihetarylthioethers target the coenzyme A synthesis pathway in Plasmodium falciparum erythrocytic stages |
title_full |
Antiplasmodial dihetarylthioethers target the coenzyme A synthesis pathway in Plasmodium falciparum erythrocytic stages |
title_fullStr |
Antiplasmodial dihetarylthioethers target the coenzyme A synthesis pathway in Plasmodium falciparum erythrocytic stages |
title_full_unstemmed |
Antiplasmodial dihetarylthioethers target the coenzyme A synthesis pathway in Plasmodium falciparum erythrocytic stages |
title_sort |
antiplasmodial dihetarylthioethers target the coenzyme a synthesis pathway in plasmodium falciparum erythrocytic stages |
publisher |
BMC |
series |
Malaria Journal |
issn |
1475-2875 |
publishDate |
2017-05-01 |
description |
Abstract Background Malaria is a widespread infectious disease that threatens a large proportion of the population in tropical and subtropical areas. Given the emerging resistance against the current standard anti-malaria chemotherapeutics, the development of alternative drugs is urgently needed. New anti-malarials representing chemotypes unrelated to currently used drugs have an increased potential for displaying novel mechanisms of action and thus exhibit low risk of cross-resistance against established drugs. Results Phenotypic screening of a small library (32 kinase-inhibitor analogs) against Plasmodium falciparum NF54-luc asexual erythrocytic stage parasites identified a diarylthioether structurally unrelated to registered drugs. Hit expansion led to a series in which the most potent congener displayed nanomolar antiparasitic activity (IC50 = 39 nM, 3D7 strain). Structure–activity relationship analysis revealed a thieno[2,3-d]pyrimidine on one side of the thioether linkage as a prerequisite for antiplasmodial activity. Within the series, the oxazole derivative KuWei173 showed high potency (IC50 = 75 nM; 3D7 strain), good solubility in aqueous solvents (1.33 mM), and >100-fold selectivity toward human cell lines. Rescue experiments identified inhibition of the plasmodial coenzyme A synthesis as a possible mode of action for this compound class. Conclusions The class of antiplasmodial bishetarylthioethers reported here has been shown to interfere with plasmodial coenzyme A synthesis, a mechanism of action not yet exploited for registered anti-malarial drugs. The oxazole congener KuWei173 displays double-digit nanomolar antiplasmodial activity, selectivity against human cell lines, high drug likeness, and thus represents a promising chemical starting point for further drug development. |
topic |
Anti-malaria drugs Coenzyme A synthesis Drug discovery Malaria 1,3,4-Oxadiazole Oxazole |
url |
http://link.springer.com/article/10.1186/s12936-017-1839-3 |
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