Identification of Coumarin-Chalcone and Coumarin-Pyrazoline Derivatives as Novel Anti-Toxoplasma gondii Agents

Introduction: Toxoplasmosis, a zoonotic infection caused by the apicomplexan parasite Toxoplasma gondii , affects a significant portion of the global human population. This condition, particularly dangerous for pregnant women and immunocompromised individuals, currently lacks effective treatment options. Methods: Eighteen coumarin-based derivatives were synthesized, comprising coumarin-chalcone hybrids (5a-i) and coumarin-pyrazoline hybrids (6a-i). Cytotoxicity was evaluated using L929 mouse fibroblasts and Hs27 human fibroblasts. Anti- T. gondii activity was assessed, and molecular docking studies were performed to predict binding modes with TgCDPK1. Results: Pyrazoline hybrids (6a-i) showed lower toxicity than chalcone-bearing coumarins (5a-i), with CC 30 values exceeding the highest tested concentration (500 μg/mL) for most compounds. The synthesized molecules demonstrated strong anti- T. gondii activity, with IC 50 values ranging from 0.66 μg/mL to 9.05 μg/mL. Molecular docking studies provided insights into potential binding mechanisms. Conclusion: This study highlights the potential of coumarin-based hybrids as anti- T. gondii agents. The findings should contribute to the growing arsenal of small molecules against T. gondii and underscore the value of molecular hybridization in drug design. Further studies to elucidate these compounds' mechanism of action and in vivo efficacy are warranted to fully realize their potential as anti-parasitic agents. Keywords: Coumarin sulfonamides, Synthesis, N-acetylpyrazoline, TgCDPK1 enzyme, molecular docking