A copper(II)-binding triazole derivative with ionophore properties is active against Candida spp

Area of Science:

• Medicinal Chemistry
• Antimicrobial Drug Discovery
• Molecular Biology

Background:

• Invasive fungal infections (IFIs) pose significant life-threatening risks.
• Existing antifungal therapies face limitations due to side effects and emerging resistance.
• Azole antifungals are common treatments, with copper showing potential synergistic effects.

Purpose of the Study:

• To design and synthesize a novel compound integrating azole and copper(II)-binding functionalities.
• To investigate the molecular mechanisms of biological toxicity for the designed compound and its copper(II) complex.
• To evaluate the potential of this bifunctional approach for developing new antifungal agents.

Main Methods:

• Synthesis of a novel compound (4) incorporating azole and copper(II)-binding groups.
• Preparation and characterization of the copper(II) complex (Cu.4).
• Antifungal activity testing against Candida spp.
• Investigation of molecular mechanisms including reactive oxygen species (ROS) generation, iron chelation, and cellular toxicity assays (macrophages, HeLa cells).

Main Results:

• Both compound 4 and its copper(II) complex, Cu.4, demonstrated activity against Candida spp.
• Cu.4 functions as a copper(II) ionophore, leading to intracellular reactive oxygen species (ROS) accumulation.
• Compound 4 acts as an iron chelator, reducing iron bioavailability and exerting toxicity.
• Cu.4 exhibited significant toxicity to macrophages and HeLa cells, unlike compound 4.

Conclusions:

• The combination of azoles with copper offers a novel strategy for developing bifunctional antifungals.
• Cu.4 disrupts fungal homeostasis by deregulating copper levels and inducing oxidative stress.
• This approach opens new avenues for combating invasive fungal infections by targeting multiple pathways.