Thieno[3,2-b]pyrrole 5-carboxamides as potent and selective inhibitors of Giardia duodenalis

Christopher JS Hart; Andrew G. Riches; Snigdha Tiash; Rebecca Abraham; Keely Fayd’Herbe; Ellis Joch; Bilal Zulfiqar; Melissa L. Sykes; Vicky M. Avery; Jan Šlapeta; Sam Abraham; John H. Ryan; Tina S. Skinner-Adams

doi:10.1016/j.ijpddr.2023.09.002

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Thieno[3,2-b]pyrrole 5-carboxamides as potent and selective inhibitors of Giardia duodenalis

Journal article

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Thieno[3,2-b]pyrrole 5-carboxamides as potent and selective inhibitors of Giardia duodenalis

Christopher JS Hart, Andrew G. Riches, Snigdha Tiash, Rebecca Abraham, Keely Fayd’Herbe, Ellis Joch, Bilal Zulfiqar, Melissa L. Sykes, Vicky M. Avery, Jan Šlapeta, …

International Journal for Parasitology: Drugs and Drug Resistance, Vol.23, pp.54-62

2023

DOI: https://doi.org/10.1016/j.ijpddr.2023.09.002

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Abstract

Giardia duodenalis is the causative agent of the neglected diarrhoeal disease giardiasis. While often self-limiting, giardiasis is ubiquitous and impacts hundreds of millions of people annually. It is also a common gastro-intestinal disease of domestic pets, wildlife, and livestock animals. However, despite this impact, there is no vaccine for Giardia currently available. In addition, treatment relies on chemotherapies that are associated with increasing failure rates. To identify new treatment options for giardiasis we recently screened the Compounds Australia Scaffold Library for new chemotypes with selective anti-Giardia activity, identifying three compounds with sub-μM activity and promising selectivity. Here we extended these studies by examining the anti-Giardia activity of series CL9569 compounds. This compound series was of interest given the promising activity (IC50 1.2 μM) and selectivity demonstrated by representative compound, SN00798525 (1). Data from this work has identified an additional three thieno [3,2-b]pyrrole 5-carboxamides with anti-Giardia activity, including 2 which displayed potent cytocidal (IC50 ≤ 10 nM) and selective activity against multiple Giardia strains, including representatives from both human-infecting assemblages and metronidazole resistant parasites. Preclinical studies in mice also demonstrated that 2 is well-tolerated, does not impact the normal gut microbiota and can reduce Giardia parasite burden in these animals.

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Title: Thieno[3,2-b]pyrrole 5-carboxamides as potent and selective inhibitors of Giardia duodenalis
Authors/Creators: Christopher JS Hart - Griffith University
Andrew G. Riches
Snigdha Tiash - Griffith University
Rebecca Abraham - Murdoch University
Keely Fayd’Herbe - Griffith University
Ellis Joch - Griffith University
Bilal Zulfiqar - Griffith University
Melissa L. Sykes - Griffith University
Vicky M. Avery - Griffith University
Jan Šlapeta - The University of Sydney
Sam Abraham - Murdoch University
John H. Ryan
Rebecca Abraham - Murdoch University, Centre for Biosecurity and One Health
Tina S. Skinner-Adams
Publication Details: International Journal for Parasitology: Drugs and Drug Resistance, Vol.23, pp.54-62
Publisher: Elsevier Ltd on behalf of Australian Society for Parasitology
Identifiers: 991005607769507891
Murdoch Affiliation: Harry Butler Institute
Language: English
Resource Type: Journal article

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