Synthesis and synergistic studies of isatin based mixed ligand complexes as potential antifungal therapeutic agents

Abstract

Metal based drugs are important class of chemotherapeutic agents that have the potential to circumvent drug resistance. Increasing drug resistance, treatment failures and limited treatment options necessitates the development of new therapeutic drugs with different mechanisms of action. Towards this direction, we synthesized a series of isatin based mixed ligand complexes of [Cu(dbm)LClH₂O] <b>(mlc1)</b>, [Co(dbm)LCl₂]^‒ <b>(mlc2)</b> and [Ni(dbm)LClH₂O] <b>(mlc3)</b> and evaluated their antifungal activity alone and in combination with fluconazole (FLC) against seven different <i>Candida albicans</i> isolates. The insight mechanism of antifungal action was revealed by studying apoptosis via terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. The study revealed that all these compounds showed antifungal activity at varying concentrations with <b>mlc3</b> as the most potent compound with minimum inhibitory concentration ranging from 0.5-8 μg/mL and minimum fungicidal concentration ranging from 4-16 μg/mL. Upon combination with FLC, most of the interactions were either synergistic (54 %) or additive (32 %) with no antagonistic combination against any of the tested isolate. The study on their mechanism of action revealed that these compounds show apoptotic effect on <i>C. albicans</i> at sub-inhibitory concentrations, suggesting that strategies to target this process may augment the current antifungal treatment modalities.