Heteroleptic transition metal complexes of Schiff‐base‐derived ligands exert their antifungal activity by disrupting membrane integrity

Abstract

Development of new treatment strategies and chemotherapeutic agents isurgently needed to combat the growing multidrug resistant species of Candida. In this direction, a new series of Cu (II), Co (II), Ni (II) and Zn (II) heteroleptic complexes were synthesized, characterized and evaluated for antifungal activity. Based on spectral characterization and physical measurements, an octahedral geometry was assigned to [Co(L1)(L2)All the synthesized compounds were tested for antifungal activity against 11 Candida albicans isolates, including fluconazole (FLC)-resistant isolates, by determining minimum inhibitory concentrations (MIC) and minimum fungicidal concentrations (MFC), following CLSI guidelines. The mechanism of their antifungal activity was assessed by studying their effect on the plasma membrane using flow cytometry and quantifying the ergosterol contents. All the test compounds showed varying levels of antifungal activity. Both the ligands showed moderate antifungal activity with a median MIC value of 100 μg/mL with no fungicidal activity. Compound C3 was the most potent compound with median MIC and MFC values of 0.10 and 1.60 μg/mL, respectively. Flow cytometry analysis revealed that these compounds at MFC values disrupt the cell membrane, resulting in propidium iodide entering the cells. These compounds also reduced a considerable amount of ergosterol content after treating the cells with MIC and sub-MIC values. This study indicates that these compounds have high antifungal activity against C. albicans, and have the potential to be developed as novel antifungal drugs.

Metallodrugs are unique: opportunities and challenges of discovery and development

“…However, more mechanistic studies are required with these ligands to allow more detailed comparisons of their mechanisms of action. 160 Metal-quinoline antibiotics can exhibit good antifungal activity, and 1,10-phenanthroline conjugated to Mn II , Ag I and Cu II inhibit growth of drug-resistant biolms and planktonic fungi species that lead to the Candida haemulonii complex. Their mechanisms of action may include DNA and protein cleavage, mitochondrial disruption and interference with protein synthesis.…”

Equilibria in Aqueous Cobalt(II)—Reduced Schiff Base N-(2-hydroxybenzyl)alanine System: Chemical Characterization, Kinetic Analysis, Antimicrobial and Cytotoxic Properties

“…They are also popular ligands for antiradical and antioxidant complexes [ 1 , 4 ]. In addition, Schiff base complexes exhibit anti-inflammatory [ 10 ], antibacterial [ 11 , 12 ], antifungal [ 13 ], anticarcinogenic [ 14 , 15 , 16 , 17 , 18 ], catecholase [ 19 , 20 ] activities and DNA-binding ability [ 21 , 22 ].…”

Synthesis, structural characterization, density functional theory calculations, and antimicrobial, anticancer, and antimetastatic properties of nanosized heteroleptic complexes of cocaine/TMEDA with d‐block metal ions

“…In this context, heteroleptic transition metal complexes, which contain two or more different ligands, have gained particular attention as an important category of transition metal complexes [ 23–28 ] because of the stepwise dissociation during the formation of metal–DNA complexes, which enhances the cellular uptake and consequently the anticancer activity. [ 29,30 ]…”

“…In this context, heteroleptic transition metal complexes, which contain two or more different ligands, have gained particular attention as an important category of transition metal complexes [23][24][25][26][27][28] because of the stepwise dissociation during the formation of metal-DNA complexes, which enhances the cellular uptake and consequently the anticancer activity. [29,30] The azabicyclo[3.2.1]octane moiety composes the core structure of various biologically active compounds with antiproliferative, antimicrobial, analgesic, and antiinflammatory effects that are occasionally exploited as drugs.…”