Synthesis and Anti- Trypanosoma cruzi Activity of 3-Cyanopyridine Derivatives

SLAFER, BRIAN W.; DESSOY, MARCO A.; DE OLIVEIRA, RAMON G.; MOLLO, MARIA C.; LEE, EUN; MATHEEUSSEN, AN; MAES, LOUIS; CALJON, GUY; FERREIRA, LEONARDO L. G.; KROGH, RENATA; ANDRICOPULO, ADRIANO D.; CRUZ, LUIZA R.; MOWBRAY, CHARLES E.; KRATZ, JADEL M.; DIAS, LUIZ C.

ACS Omega

American Chemical Society

Año: 2024

2470-1343

Chagas disease (CD) is a parasitic neglected tropical disease (NTD) caused by the protozoan Trypanosoma cruzi that affects 6 million people worldwide, often resulting in financial burden, morbidity, and mortality in endemic regions. Given a lack of highly efficient and safe treatments, new, affordable, and fit-for-purpose drugs for CD are urgently needed. In this work, we present a hit-to-lead campaign for novel cyanopyridine analogues as antichagasic agents. In a phenotypic screening against intracellular T. cruzi, hits 1 and 2 were identified and displayed promising potency combined with balanced physicochemical properties. As part of the Lead Optimization Latin America consortium, a set of 40 compounds was designed, synthesized, and tested against T. cruzi intracellular amastigotes and relevant human cell lines. The structural modifications were focused on three positions: cyanopyridine core, linker, and right-hand side. The ADME properties of selected compounds, lipophilicity, kinetic solubility, permeability, and liver microsomal stability, were evaluated. Compounds 1–9 displayed good potency (EC50 T. cruzi amastigote