Highly Selective Thiazole Derivatives as Promising Anti- Toxoplasma gondii Agents

Abstract Toxoplasmosis, caused by the protozoan Toxoplasma gondii, remains a significant global health challenge, particularly for immunocompromised individuals. Current therapies, based on pyrimethamine and sulfadiazine, are limited by toxicity, suboptimal efficacy, and the emergence of resistant parasite strains, highlighting the need for safer and more effective alternatives. In this study, we evaluated the antiparasitic potential of six 2-pyridyl 1,3-thiazole derivatives─privileged scaffolds previously reported for potent antitumor activity but never investigated against T. gondii. In vitro assays were performed using intracellular tachyzoites of the RH strain and human foreskin fibroblasts to determine antiparasitic activity and host-cell cytotoxicity. The derivatives exhibited half-maximal effective concentrations (EC50) between 212 and 490 nM and cytotoxicity values (CC50) ranging from 1.5 to 48 μM. One compound, TAP-05, demonstrated a notable selectivity index of 183.26, exceeding that of the reference drug pyrimethamine, supporting its potential as a lead candidate for further optimization. Transmission electron microscopy of treated parasites revealed reduced ultrastructural signs of tachyzoite division and increased cytoplasmic vacuolization compared to untreated controls, along with occasional Golgi perturbations. These qualitative observations raise the hypothesis of a cytostatic effect of TAP-05 on parasite replication, which requires confirmation by dedicated functional assays. These findings identify a promising thiazole-based chemotype for toxoplasmosis drug discovery and warrant additional studies to elucidate mechanisms of action and assess in vivo efficacy.