title: Adamantylidene-substituted alkylphosphocholine TCAN26 is more active against Sporothrix schenckii than miltefosine.
abstract: Sporotrichosis is the most frequent subcutaneous mycosis in the world and its increasing incidence has led to the search for new therapeutic options for its treatment. In this study, we demonstrated that three structural analogues of miltefosine (TCAN26, TC19, and TC70) showed inhibitory activity against Sporothrix schenckii sensu stricto and that TCAN26 was more active in vitro than miltefosine against several isolates. Scanning electron microscopy showed that S. schenckii exposure to TCAN26 resulted in cells that were slightly more elongated than untreated cells. Transmission electron microscopy showed that TCAN26 treatment induced loss of the regular cytoplasmic electron-density and altered the cell envelope (disruption of the cell membrane and cell wall, and increased cell wall thickness). Additionally, TCAN26 concentrations required to kill S. schenckii cells were lower than concentrations that were cytotoxic in mammalian cells, and TCAN26 was more selective than miltefosine. Thus, the adamantylidene-substituted alkylphosphocholine TCAN26 is a promising molecule for the development of novel antifungal compounds, although further investigations are required to elucidate the mode of action of TCAN26 in S. schenckii cells.
authors: Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, Instituto de Biofísica Carlos Chagas Filho, Laboratório de Biologia Celular de Fungos, Rio de Janeiro, RJ, Brasil.
authors: Luana Pereira
authors: LP
authors: Borba-Santos
authors: Universidade de São Paulo, Instituto de Ciências Biomédicas, São Paulo, SP, Brasil.
authors: Kelly
authors: K
authors: Ishida
authors: National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
authors: Theodora
authors: T
authors: Calogeropoulou
authors: Universidade Federal do Rio de Janeiro, Instituto Nacional de Ciência e Tecnologia de Biologia Estrutural e Bioimagem, Rio de Janeiro, RJ, Brasil.
authors: Wanderley de
authors: Wd
authors: Souza
authors: Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, Instituto de Biofísica Carlos Chagas Filho, Laboratório de Biologia Celular de Fungos, Rio de Janeiro, RJ, Brasil.
authors: Sonia
authors: S
authors: Rozental
mesh_terms: D000218:Adamantane / Q000737:chemistry / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects; D057915:Drug Substitution; D006801:Humans; D008826:Microbial Sensitivity Tests; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013175:Sporothrix / Q000145:classification / Q000187:drug effects* / Q000648:ultrastructure
chemical_list: D000935:Antifungal Agents; D010767:Phosphorylcholine; C039128:miltefosine; C020855:adamantylidene; D000218:Adamantane