Tetrazole derivatives bearing benzodiazepine moiety-synthesis and action mode against virulence of Candida albicans

Tetrazole and benzodiazepine derivatives attract widespread attention due to their remarkable pharmaceutical potential. 5-(2-bromophenyl)-7-fluoro-1-[3-(5-(4-chlorophenyl)-2H-tetrazol-2-yl)propyl]-1,3-dihydro-2H-1,4-benzodiazepin-2-one (6c) and 5-(2-bromophenyl)-7-fluoro-1-[3-(5-(2-chlorophenyl)-2H-tetrazol-2-yl)propyl]-1,3-dihydro-2H-1,4-benzodiazepin-2-one (6d) were selected using the microdilution approach and because of their preferential fungicidal activity toward C. albicans. 6c or 6d altered the hyphal morphology, chitin deposition and membrane permeation in planktonic and sessile cells. The tetrazoles caused PS translocation and the accidental dependent permeabilization (ADP) of sessile cells; 6d showed CNB1-dependent action in candidiasis. The exosome Rh123-rich vesicles extruded out of the membrane as an element of the self-defense detoxification strategy when the treatment, especially with 6d, was conducted. The tetrazoles affected the C. albicans biofilm's viability, and Rh123 sequestrates led to a heterogenous sub-cellular localization. While 6c-dependent sequestration into membranes or sub-cellular organelles was noted, Rh123 cellular loading in control cells and distributed within cells was observed (partitioning into subcellular membranes and organelles in apoptotic cells). In conclusion, we propose new agents aimed at Candida virulence factors triggering ACD without toxicity against eukaryotic cells.