Synthesis and antifungal screening of tetramethyl hexahydro-1H-xanthene-1,8(2H)-dione derivatives as potential inhibitors of morphogenesis and biofilm formation in Candida albicans

Biofilms formed by the Candida albicans species are very challenging to control because of their resistance to existing antifungal drugs, and new therapeutic agents to tackle this problem are highly desired. A series of hexahydro-1H-xanthene-1,8(2H)-dione (XDs 1-10) derivatives were synthesized via the condensation reaction of dimedone and aromatic aldehydes using ZSM-5 zeolite as a catalyst. The structure of the synthesized derivatives was confirmed via spectrometric analysis. All the XD derivatives were screened for their anti-virulence properties, viz., the inhibition of biofilm formation, morphogenesis, and adhesion against Candida albicans. Derivatives XD-2, 4, 5, and 6 demonstrated potential activity of biofilm and morphogenesis inhibition at concentrations of 47.34-107.10 mu M and showed adhesion inhibition at 25 mu M concentration. The anti-virulence mechanism of the active XD derivatives was studied by measuring the gene expression, and hwp1, ras1, nrg1, and als6 genes were found to be down-regulated in the presence of XD-4 and XD-6 derivatives. The molecular docking analysis of XD-4 and XD-6 revealed that both derivatives bind at the active site of SAP5 with binding energies of -9.77 and -10.04 kcal mol(-1), respectively, and remain stable throughout the molecular dynamic simulations. The active derivatives XD-2, 4, 5, and 6 were further evaluated for their cytotoxicity against the epithelial cell line derived from the human kidney embryo (HEK 293) and were found to be non-toxic. The potential biofilm, morphogenesis, and adhesion inhibition activity suggested that these xanthene derivatives could aid and assist in the development of lead compounds to treat fungal infections and virulence attributes.