Imidazopyridine derivatives as promising anti-Toxoplasma gondii agents: in vitro studies, in vivo testing, and molecular modeling analysis.

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Abstract
Toxoplasmosis continues to pose significant challenges to public health and animal husbandry, thereby generating an ongoing need for the development of novel therapies through innovative approaches. In response to the persistent pursuit of an optimal chemotherapeutic agent, the present study designed and synthesized new small molecules (6 and 9a-d) featuring an imidazopyridine scaffold linked to isatin derivatives via a hydrazide moiety. The efficacy of these compounds was evaluated against Toxoplasma gondii (ME49 strain) in both in vitro and in vivo murine models of chronic infection. Notably, most of the tested compounds exhibited significant antiparasitic activity. Compound 9a showed the lowest calculated LD50 value, indicating strong potency, while compound 9c demonstrated excellent cysticidal activity in vitro, achieving 100% cyst mortality at concentrations ≥100 µg mL-1. In vivo, compound 9c was the most effective treatment, reducing brain cyst burden by 82.7%. Molecular analyses indicated that compound 9c significantly reduced T. gondii DNA levels and strongly downregulated pro-inflammatory cytokines. Molecular docking analyses further validated the effective interactions between the synthesized compounds and the target enzyme T. gondii calcium-dependent protein kinase-1 (TgCDPK1). Collectively, these results highlight the promising anti-Toxoplasma potential of imidazopyridine-isatin hybrids, which provides a foundation for the further development of these hybrid molecules as therapeutic agents against toxoplasmosis.

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