Synthesis of amino acid appended indoles: Appreciable anti-fungal activity and inhibition of ergosterol biosynthesis as their probable mode of action

•A series of rationally designed novel compounds is prepared.•Some of the compounds exhibited significant inhibition of growth of Candida sp.•Lanosterol 14α-demethylase seems to be the probable cellular target of the compounds.

Rationally designed compounds consisting of mono- and di-peptide appendages on bis-indole template were synthesized in appreciable yield. Some of these compounds exhibited significant antifungal activities against Candida albicans with their MIC80 in μg/ml range. However, when used in combination with azoles, the antifungal activities of the azoles were considerably enhanced. The growth inhibition appeared to be specific to the fungal cells and mammalian cells were not affected by these compounds. It is shown that these compounds lower ergosterol levels in the fungal cells and probably act by targeting lanosterol 14α-demethylase, a key enzyme in the sterol biosynthetic pathway of C. albicans. The compounds do not appear to directly act on the fungal cell wall. Hence, the sensitivity of the fungal cells to these compounds cannot be attributed to cell wall damage and consequent accumulation of the compounds in the cell, though defects in cell wall due to defective sterol biosynthesis cannot be completely ruled out.

Graphical abstractCompounds with appreciable fungal growth inhibition are identified. Erg11 seems to be their probable cellular target. Figure optionsDownload full-size imageDownload as PowerPoint slide