Synergistic antifungal effect of cyclized chalcone derivatives and fluconazole against Candida albicans

Abstract

The occurrence of invasive fungal diseases, particularly in immunocompromised patients, is life-threatening and increases the economic burden. The rising problem of multi-drug resistance is becoming a major concern for clinicians. In addition, a repertoire of antifungal agents is far less in number than antibacterial drugs. To combat these problems, combination therapy has gained a lot of interest. We previously reported the synergistic interaction of some mono- and bis-dihydropyrimidinone and thione derivatives with fluconazole and amphotericin B for combination antifungal therapy. In this study we used the same approach and synthesized different azole and non-azole derivatives of mono-() and bis-() chalcones and evaluated their antifungal activity profile alone and in combination with the most commonly used antifungal drug - fluconazole (FLC) - against seven FLC susceptible and three FLC resistant clinically isolated strains. Based on the minimum inhibitory concentration results, the bis-derivatives showed lower MIC values compared to their mono-analogues. Both fractional inhibitory concentration index and isobologram results revealed mostly synergistic, additive or indifferent interactions between the tested compounds and FLC against different isolates. None of the tested compounds showed any effect on energy dependent R6G efflux, revealing that they do not reverse the mechanism of drug efflux. However, surprisingly, these compounds profoundly decreased ergosterol biosynthesis and showed down regulation of gene expression, which is the possible mechanism of reversal of azole drug resistance by these compounds. These results provide a platform for further research to develop pyrimidinone/thione ring containing compounds as promising new antifungal agents, which could be used in antifungal combination therapy.

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

“…DBM has also been found as a possible candidate for dementia treatment [11]. Based on our previous studies it is our premise that complexation of bioactive ligands with transition metals and combination therapy greatly improves the treatment efficacy and provides a broader treatment window that greatly helps to circumvent drug resistance [12, 13, 14]. In this study, we proposed to prepare some mixed ligand complexes of a ligand derived from isatin and DBM as a co-ligand and tested them against different FLC susceptible and resistant C. albicans isolates alone and in combination with FLC to obtain new antifungal agents or potentiators that could be used in combination therapy.…”

Performance of a new Candida anti-mannan IgM and IgG assays in the diagnosis of candidemia

“…Candida is one of the leading causes of healthcare-associated bloodstream infections. Owing to the advances in medical technology, the application of invasive procedures is becoming more and more extensive, increasing significantly the burden of Candida infections, especially in critically ill patients 1,2 . Early initiation of effective antifungal therapy was essential to improve the outcome of patients, while misdiagnosis or delay in diagnosis of candidemia could result in substantial morbidity and mortality (as high as 46-75%) 3 , so the early diagnosis of candidemia is of great value.…”

Synthesis, biological evaluation and molecular docking study of dihydropyrimidine derivatives as potential anticancer agents

“…The pyrimidine system is an important pharmacophore with abundant occurrence in nature. Natural and synthetic dihydropyrimidine derivatives have a wide range of pharmacological actions, such as antifungal, anticonvulsant, antitubercular, anti‐inflammatory, and antiviral . Several drugs have been developed from tetrahydropyrimidine derivatives like sildenafil, which is an inhibitor of phosphodiesterase.…”