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

Manal S Ebaid,1,2 Maciej Chyb,3,4 Veronika Furlan,5 Hoda Atef Abdelsattar Ibrahim,6 Urban Bren,5,7,8 Justyna Gatkowska,3 Jarosław Dziadek,9 Wagdy M Eldehna,10,11 Ahmed Sabt2 1Department of Chemistry, College of Science, Northern Border University, Arar, Saudi Arabia; 2Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Center, Dokki, Cairo, Egypt; 3Department of Molecular Microbiology, Faculty of Biology and Environmental Protection, University of Lodz, Łódź, Poland; 4Bio-Med-Chem Doctoral School of the University of Lodz and Lodz Institutes of the Polish Academy of Sciences, Łódź, Poland; 5Faculty of Chemistry and Chemical Engineering, University of Maribor, Maribor, Slovenia; 6Pediatric Department, Faculty of Medicine, Cairo University, Cairo, Egypt; 7Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska, Glagoljaška 8, Slovenia; 8Institute of Environmental Protection and Sensors, Beloruska Ulica 7, Maribor, Slovenia; 9Laboratory of Genetics and Physiology of Mycobacterium, Institute of Medical Biology of the Polish Academy of Sciences, Łódź, Poland; 10Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt; 11Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, EgyptCorrespondence: Ahmed Sabt; Wagdy M Eldehna, Email [email protected]; [email protected]: 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 CC30 values exceeding the highest tested concentration (500 μg/mL) for most compounds. The synthesized molecules demonstrated strong anti-T. gondii activity, with IC50 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