by Slafer BW, Dessoy MA, de Oliveira RG, Mollo MC, Lee E, Matheeussen A, Maes L, Caljon G, Ferreira LLG, Krogh R, Andricopulo AD, Cruz LR, Mowbray CE, Kratz JM, Dias LC. ACS Omega 2024. doi: 10.1021/acsomega.4c01919
Summary: The authors of this manuscript present a hit-to-lead campaign for novel cyanopyridine analogues active against Trypanosoma cruzi, the causative agent of Chagas disease. Two hits were identified that had promising potency and balanced physicochemical properties. Within the Lead Optimization Latin America (LOLA) consortium, structural modifications were made to one of these hits, resulting in a set of 40 compounds that was designed, synthesized, and tested against T. cruzi intracellular amastigotes and relevant human cell lines. Nine of the compounds had good potency and most were not significantly cytotoxic. However, despite the good balance between potency and selectivity, the antiparasitic activity appeared to be driven by lipophilicity, making progression of the series unfeasible.
