Searching for new agents active against Candida albicans biofilm: A series of indole derivatives, design, synthesis and biological evaluation

Candida albicans biofilm represents a major clinical problem due to its intrinsic tolerance to anti-fungal compounds and it has been highly related to infections in catheterized patients. Few compounds are described as able to inhibit biofilm formation or to interfere with preformed biofilm of C. albicans. Here we report the in vitro evaluation of anti-biofilm activity on C. albicans ATCC 10231 of a series of new and already known amine and amide indole derivatives. Among the studied compounds, fifteen resulted active on C. albicans ATCC 10231 biofilm, with BMIC₅₀ ≤ 16 μg/mL. Three of them (7, 23 and 33) showed a selectivity towards mature biofilm and the most active of them was the compound 23 (BMIC₅₀ = 4 μg/mL). On the other hands, two different compounds (21 and 22) were selective towards biofilm formation with BMIC₅₀ values of 8 μg/mL. Otherwise, compounds 16 and 17 resulted active on biofilm formation, with BMIC₅₀ of 8 μg/mL and 2 μg/mL respectively, and on mature biofilm with BMIC₅₀ of 2 μg/mL. These two last compounds also showed an interesting activity towards the planktonic cells of C. albicans. A selection of the more active compounds was also evaluated on different C. albicans strains (PMC1042, PMC1083 and ATCC 10261), showing a comparable or higher anti-biofilm activity, especially on mature biofilm. In vivo toxicity studies using the Galleria mellonella larvae, were finally carried out on more active indole derivatives, showing that they are poorly toxic even at the highest concentrations tested (500-1000 μg/mL).