Discovery and Evaluation of SA ‐18 as an Anti‐ Toxoplasma Agent

ABSTRACT Toxoplasma gondii , a globally prevalent apicomplexan parasite, causes severe morbidity and mortality in immunocompromised individuals and livestock. Current therapies exhibit limited efficacy against chronic bradyzoite stages and face drug resistance. Here, we screened imidocarb and its derivatives for anti‐ Toxoplasma activity. Among 20 synthesized compounds, squaramide derivative 18 (SA‐18) emerged as a promising candidate with nanomolar EC 50 against tachyzoites, potent inhibition of bradyzoite differentiation, and > 100‐fold selectivity index. Transcriptomic analysis revealed transcriptional dysregulation in parasite metabolic pathways and downregulation of bradyzoite marker BAG1. In vivo studies exhibited significant parasite load reduction in murine models, albeit with suboptimal survival rates. These findings highlight SA‐18 as a novel candidate for toxoplasmosis therapy, warranting further optimization for clinical translation.