Nontoxic Cobalt(III) Schiff Base Complexes with Broad-Spectrum Antifungal Activity.

Angelo Frei,Amy K Cain,Francesca L Short,A Paden King,Hue Dinh,Johannes Zuegg,Gabrielle J Lowe,Mark A T Blaskovich,Justin J Wilson,Alysha G Elliott

doi:10.1002/chem.202003545

Angelo Frei, Amy K Cain + Show 8 more

Open Access

https://doi.org/10.1002/chem.202003545

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Abstract

Resistance to currently available antifungal drugs has quietly been on the rise but overshadowed by the alarming spread of antibacterial resistance. There is a striking lack of attention to the threat of drug‐resistant fungal infections, with only a handful of new drugs currently in development. Given that metal complexes have proven to be useful new chemotypes in the fight against diseases such as cancer, malaria, and bacterial infections, it is reasonable to explore their possible utility in treating fungal infections. Herein we report a series of cobalt(III) Schiff base complexes with broad‐spectrum antifungal activity. Some of these complexes show minimum inhibitory concentrations (MIC) in the low micro‐ to nanomolar range against a series of Candida and Cryptococcus yeasts. Additionally, we demonstrate that these compounds show no cytotoxicity against both bacterial and human cells. Finally, we report the first in vivo toxicity data on these compounds in Galleria mellonella, showing that doses as high as 266 mg kg−1 are tolerated without adverse effects, paving the way for further in vivo studies of these complexes.

Highlights

The human body is well equipped to fight off most primary fungal infections as the combination of high body temperature and a sophisticated immune system make it difficult for fungi to colonise the human body
Gałczyńska et al reported a series of copper(II) and cobalt(II) complexes with the ligands imidazole-4-acetate and 1-allylimidazole and found that the Co(II)-iaa compound (Co2) showed a significant reduction (~5 log) in colony forming units (CFU) against Candida albicans at 60 μM in vitro, while not displaying any cytotoxicity at the same concentration
We found that metal complexes had a 10× higher hit-rate against critical bacterial ESKAPE pathogens and yeasts, compared to the 300,000 organic compounds in the collection, while displaying similar rates for cytotoxicity and haemolysis

Summary

Introduction

The human body is well equipped to fight off most primary fungal infections as the combination of high body temperature and a sophisticated immune system make it difficult for fungi to colonise the human body. We report a series of cobalt(III) Schiff base complexes with broad spectrum antifungal activity.

Results

Conclusion