Antiplasmodial dihetarylthioethers target the coenzyme A synthesis pathway in Plasmodium falciparum erythrocytic stages

Malaria Journal
Thomas WeidnerConrad Kunick

Abstract

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. 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 inhibiti...Continue Reading

References

Jan 12, 2008·Journal of Medicinal Chemistry·Christina ReichwaldConrad Kunick
Nov 11, 2008·Current Drug Metabolism·Edward H KernsGuy T Carter
Jul 9, 2009·The Journal of Biological Chemistry·Christina Spry, Kevin J Saliba
Jul 31, 2009·The New England Journal of Medicine·Arjen M DondorpNicholas J White
Nov 13, 2009·Malaria Journal·Nicholas J WhiteNicholas P J Day
May 21, 2010·Nature·David A Fidock
May 21, 2010·Nature·Francisco-Javier GamoJose F Garcia-Bustos
Sep 3, 2010·BMC Systems Biology·Carola HuthmacherHermann-Georg Holzhütter
Jan 11, 2012·The American Journal of Tropical Medicine and Hygiene·Sandra Duffy, Vicky M Avery
May 8, 2013·European Journal of Medicinal Chemistry·Jasmin RyczakConrad Kunick
Jun 8, 2013·Malaria Journal·Jeremy N BurrowsTimothy N C Wells
Oct 13, 2011·ACS Medicinal Chemistry Letters·Félix CalderónJulia Castro
Jan 20, 2015·Nature Genetics·Olivo MiottoDominic P Kwiatkowski
May 23, 2015·Nature Reviews. Drug Discovery·Timothy N C WellsWesley C Van Voorhis
Nov 29, 2015·Nucleic Acids Research·UNKNOWN SIB Swiss Institute of Bioinformatics Members

❮ Previous
Next ❯

Citations

Dec 25, 2019·Expert Opinion on Drug Discovery·Hanh H T NguyenMichael F Duffy
Mar 23, 2019·Malaria Journal·Andreas MaschConrad Kunick
Mar 27, 2021·Frontiers in Cellular and Infection Microbiology·Arif NurkantoTomoyoshi Nozaki
Jul 30, 2021·PLoS Pathogens·Erick T TjhinKevin J Saliba
Aug 28, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Duc Hoàng LandeConrad Kunick
Dec 31, 2021·PLoS Pathogens·Laura E de VriesDominique Soldati-Favre

❮ Previous
Next ❯

Methods Mentioned

BETA
transgenic
X-ray

Software Mentioned

GraphPad Prism
SwissADME
Excel
Office
GraphPad
Swiss ADME
Prism

Related Concepts

Related Feeds

Antimalarial Agents (ASM)

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

Antiparasitics

Antiparasitics are medications which are indicated for the treatment of parasitic diseases. Discover the latest research on antiparasitics here.

Babesiosis

Babesiosis is caused by parasites of the genus babesia, which are transmitted in nature by the bite of an infected tick. Discover the latest research on babesiosis here.

Antimalarial Agents

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.