Potent Tetrahydroquinolone Eliminates Apicomplexan Parasites

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Apicomplexan parasites cause significant global disease burden.
• Existing therapies for toxoplasmosis and malaria are limited, necessitating new treatments.

Purpose of the Study:

• To develop a next-generation anti-apicomplexan compound with improved selectivity and properties.
• To evaluate the efficacy of the novel compound JAG21 against apicomplexan parasites.

Main Methods:

• Synthesis and characterization of tetrahydroquinolone compound JAG21.
• In vitro and in vivo testing against *Toxoplasma gondii* and *Plasmodium falciparum*.
• Enzymatic, binding, and co-crystallography studies for mechanism of action and selectivity.

Main Results:

• JAG21 demonstrated significant reduction of *T. gondii* tachyzoites and bradyzoites in vitro and in murine models, achieving 100% survival.
• JAG21 showed efficacy against drug-resistant *P. falciparum* in vitro.
• Single oral dose or short-term treatment of JAG21 provided causal prophylaxis and radical cure in *P. berghei* infected mice, with 100% survival.

Conclusions:

• JAG21 exhibits potent anti-apicomplexan activity and favorable ADMET properties.
• The compound displays selectivity for apicomplexan enzymes over mammalian counterparts.
• JAG21 is a promising pre-clinical candidate for treating and preventing toxoplasmosis and malaria.