Pyridyl-Thiazole-Thiosemicarbazones as Antitrypanosomatidae Agents: Design, Synthesis, and In Silico Profiling.

Chagas disease and leishmaniasis are neglected tropical diseases caused by the trypanosomatid protozoa Trypanosoma cruzi and Leishmania spp., respectively. Currently available treatments are often insufficiently effective and lack the characteristics of ideal therapeutics. Here we report the design, synthesis, and antitrypanosomatid evaluation of 20 novel hybrid compounds incorporating pyridine, thiazole, and thiosemicarbazone scaffolds. All compounds were tested against trypomastigote and amastigote forms of T. cruzi, as well as promastigote and amastigote forms of Leishmania infantum and L. amazonensis. Cytotoxicity was assessed in L929 fibroblasts and RAW 264.7 macrophages. Compound 8 emerged as the lead, displaying an IC50 of 1.0 µM against T. cruzi and a selectivity index of 52.8. Despite its potent in vitro activity, Compound 8 exhibited poor in vivo efficacy when administered orally at 150 mg/kg/day. In silico analyses predicted strong binding to cruzain, alongside favorable bioavailability, drug-likeness, and chemical stability. Against Leishmania species, Compound 8 demonstrated selectivity comparable to miltefosine against L. amazonensis amastigotes. Collectively, these findings identify a novel chemical scaffold with promising antitrypanosomatid potential that warrants further optimization to improve in vivo performance.