1. Exploring the Antiplasmodial 2‐Aminopyridines as Potential Antitrypanosomal Agents
- Author
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Tarryn Swart, Clinton G. L. Veale, Dustin Laming, Kelly Chibale, and Heinrich C. Hoppe
- Subjects
Pharmacology ,Trifluoromethyl ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,010405 organic chemistry ,Chemistry ,Stereochemistry ,Trypanosoma brucei brucei ,Organic Chemistry ,Aminopyridines ,Trypanosoma brucei ,biology.organism_classification ,Trypanocidal Agents ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Structure-Activity Relationship ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,Parasitic Sensitivity Tests ,Drug Discovery ,Molecular Medicine ,General Pharmacology, Toxicology and Pharmaceutics - Abstract
Recently we reported the results of a screen of the Pathogen Box in which we identified 4-(2-amino-5-(4-(methylsulfonyl) phenyl) pyridin-3-yl)-2-methoxyphenol (MMV010576, 1) as our priority antitrypanosomal hit. This compound had previously been identified as a potent and selective antiplasmodial agent, where a focused optimization campaign, resulted in a medium-sized library of compounds, with favorable drug-like properties, one of which (MMV048, 2, 5-(4-(methylsulfonyl)phenyl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-2-amine) is currently undergoing clinical trials for malaria. Accordingly, we investigated this library, in order to elucidate structural activity relationship details of this class of compounds as inhibitors of Trypanosoma brucei. Our study has identified several structural features important for antitrypanosomal activity, which are distinct from those required for antiplasmodial activity. Results from this study can be exploited to develop potent antitrypanosomal agents.
- Published
- 2019
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