New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections

Area of Science:

• Parasitology
• Medicinal Chemistry
• Drug Development

Background:

• Toxoplasma gondii infection is widespread, persistent, and currently incurable, causing significant sight damage.
• There is an urgent need for new curative medicines to combat toxoplasmosis and related parasitic infections.
• Existing treatments for toxoplasmosis are limited, necessitating the development of novel therapeutic strategies.

Purpose of the Study:

• To develop novel in vitro models for T. gondii drug screening, including cyst formation and feline oocyst induction.
• To design and synthesize novel 4-(1H)-quinolone scaffolds targeting the cytochrome bc1 complex.
• To evaluate the efficacy of these novel compounds against active T. gondii infection, cysts, and drug-resistant Plasmodium falciparum.

Main Methods:

• Development of EGS strain T. gondii in vitro models for cyst formation and feline oocyst induction.
• Synthesis of novel 4-(1H)-quinolone scaffolds designed to inhibit the cytochrome bc1 complex Qi site.
• In vitro and in vivo efficacy testing of a lead compound against T. gondii and P. falciparum.
• Mutant yeast and co-crystallographic studies to elucidate the drug binding mechanism.

Main Results:

• A substituted 5,6,7,8-tetrahydroquinolin-4-one demonstrated potent inhibition of active T. gondii infection (IC50, 30 nM) and cysts (IC50, 4 μM).
• The compound showed efficacy in vivo (25 mg/kg) and against drug-resistant Plasmodium falciparum (IC50, <30 nM), with synergistic effects.
• Structural studies confirmed binding to the Qi site of the cytochrome bc1 complex.

Conclusions:

• Novel 4-(1H)-quinolone scaffolds effectively target the cytochrome bc1 complex, offering a promising therapeutic avenue.
• The developed compounds show potential for treating both toxoplasmosis and malaria, including drug-resistant strains.
• These findings have significant implications for millions infected with chronic parasitic diseases.