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

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 <1 μM),
and most compounds did not present significant cytotoxicity (CC50 MRC-5 = 32–64 μM). Despite the good balance
between potency and selectivity, the antiparasitic activity of the
series appeared to be driven by lipophilicity, making the progression
of the series unfeasible due to poor ADME properties and potential
promiscuity issues.