Cyclopalladated Complexes With Functionalized Diphosphanes as Promising Antifungal Scaffolds

Area of Science:

• Medicinal Chemistry
• Mycology
• Organometallic Chemistry

Background:

• Invasive fungal infections, particularly those caused by Candida species, represent a significant global health threat.
• Rising antifungal resistance necessitates the development of novel therapeutic agents.
• Palladium organometallic complexes have emerged as potential antifungal alternatives.

Purpose of the Study:

• To synthesize and evaluate novel cyclopalladated complexes for antifungal activity.
• To assess their efficacy against drug-resistant Candida strains and their antibiofilm properties.
• To investigate their mechanism of action, including cellular uptake and intracellular effects.

Main Methods:

• Synthesis of four cyclopalladated complexes (1a, 1b, 2a, 2b) derived from Schiff base-amine phosphanes.
• Antifungal susceptibility testing against medically relevant Candida species, including resistant strains.
• Evaluation of antibiofilm activity, cellular uptake, in vivo toxicity, and intracellular effects.
• Analysis of structure-activity relationships.

Main Results:

• Complexes 1b and 2b demonstrated significant antifungal activity against various Candida species.
• These complexes effectively overcame resistance to existing antifungal drugs and exhibited antibiofilm properties.
• Mechanistic studies revealed that 1b and 2b induce oxidative stress, lipid peroxidation, inhibit lipolysis, and disrupt vacuole integrity.
• Structure-activity relationship analysis provided insights into the design of potent palladium-based antifungals.

Conclusions:

• Palladium complexes represent a promising scaffold for the development of next-generation antifungal agents.
• The synthesized complexes, particularly 1b and 2b, exhibit potent antifungal activity through multiple mechanisms.
• Further research into palladium-based compounds could lead to novel therapeutic strategies against invasive fungal infections.