Exploring the Antiplasmodial 2‐Aminopyridines as Potential Antitrypanosomal Agents

• Published in: ChemMedChem 2019-12, Vol.14 (24), p.2034-2041
• Main Authors: Veale, Clinton G. L., Laming, Dustin, Swart, Tarryn, Chibale, Kelly, Hoppe, Heinrich C.
• Format: Article
• Language: English
• Subjects: 2-Aminopyridines; Antiprotozoal agents; Clinical trials; Human African Trypanosomiasis; Kinetoplastids; Malaria; Neglected Tropical Diseases; Optimization; Trypanosoma brucei; Vector-borne diseases
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201900492

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. Hitting a new direction: The reported optimisation of potent antiplasmodial MMV10576 resulted in a medium‐sized library of compounds with favorable properties. Having identified MMV010576 as a selective inhibitor of T. brucei, we screened this library in order to elucidate an antitrypanosomal SAR, which will assist in the development of potential lead compounds.