Synthesis of novel proxyphylline derivatives with dual Anti-Candida albicans and anticancer activity

Three out of 16 newly synthesized 1,3-dimethylxanthine derivatives (proxyphylline analogues) exhibited consistencies between antifungal and anticancer properties. Proxyphylline possessing 1-(10H-phenothiazin-10-yl)propan-2-yl (6) and polybrominated benzimidazole (41) or benzotriazole moiety (42) remained selectively cidal against Candida albicans (lg R >= 3 at conc. of 31, 36 and 20 mu M, respectively) however not against normal mammalian Vero cell line in vitro (IC50 >= 280 mu M) and Galleria mellonella in vivo. These compounds also displayed moderate antineoplastic activity against human breast adenocarcinoma (MCF-7) cell line (EC50 = 80 mu M) and high against peripheral blood T lymphoblast (CCRF-CEM) (EC50 = 6.3-6.5 mu M). In addition, 6 and 42 exerted: (1) dual activity against fungal adhesion and damage mature biofilm; (2) necrosis of planktonic cells due to loss of membrane function and of structural integrity; (3) biochemical (inhibition of sessile cell respiration) and morphological changes in cell wall polysaccharide contents. Therefore, leading proxyphylline derivatives can be employed to prevent cancer-associated biofilm Candida infections. (C) 2018 Elsevier Masson SAS. All rights reserved.