Flavonoid-Quinoxaline Hybrid Compounds as Cathepsin Inhibitors Against Fascioliasis

Area of Science:

• Parasitology
• Medicinal Chemistry
• Drug Discovery

Background:

• Fasciola hepatica infection causes significant global health and economic losses.
• Anthelmintic drug resistance in F. hepatica necessitates novel therapeutic strategies.
• Developing new fasciolicides is challenging due to the parasite's complex life cycle and limited research.

Purpose of the Study:

• To evaluate hybrid molecules combining chalcones and quinoxaline 1,4-di-N-oxides as potential fasciolicides.
• To assess the in vitro activity of these hybrids against F. hepatica cathepsin L proteases and the parasite itself.
• To investigate the binding interactions of these compounds with cathepsin targets using molecular docking.

Main Methods:

• Synthesis and in vitro testing of hybrid chalcone and quinoxaline 1,4-di-N-oxide molecules.
• Enzyme inhibition assays using isolated F. hepatica cathepsin L proteases.
• In vitro culture assays with juvenile F. hepatica parasites.
• Molecular docking studies to analyze compound-protein interactions.

Main Results:

• The hybrid molecules demonstrated potent inhibition of F. hepatica cathepsin L proteases.
• These compounds effectively killed juvenile F. hepatica parasites in vitro at micromolar concentrations.
• Molecular docking revealed that top inhibitors bind within the cathepsin active site, interacting with key catalytic residues.

Conclusions:

• Hybrid molecules integrating chalcone and quinoxaline 1,4-di-N-oxide chemotypes are effective inhibitors of F. hepatica cathepsins.
• These compounds represent promising scaffolds for developing novel fasciolicidal agents.
• Further development of these hybrid compounds could lead to new treatments for fascioliasis.