title: A novel alkyl phosphocholine-dinitroaniline hybrid molecule exhibits biological activity in vitro against Leishmania amazonensis.
abstract: Parasitic protozoa of the Leishmania genus cause leishmaniasis, an important complex of tropical diseases that affect about 12 million people around the world. The drugs used to treat leishmaniasis are pentavalent antimonials, miltefosine, amphotericin B and pentamidine. In the present study, we evaluated the effect of a novel alkyl phosphocholine-dinitroaniline hybrid molecule, TC95, against Leishmania amazonensis promastigotes and intracellular amastigotes. Antiproliferative assays indicated that TC95 is a potent inhibitor of promastigotes and intracellular amastigotes with IC50 values of 2.6 and 1.2 μM, respectively. Fluorescence microscopy with anti-α-tubulin antibody revealed changes in the cytoskeleton, whilst scanning electron microscopy showed alterations in the shape, plasma membrane, length of the flagellum, and cell cycle. Flow cytometry confirmed the cell cycle arrest mainly in G1 phase, however a significant population appeared in sub G0/G1 and super-G2. The alterations in the plasma membrane integrity were confirmed by fluorometric analysis using Sytox Blue. Transmission electron microscopy also revealed an accumulation of lipid bodies, confirmed by fluorescence microscopy and fluorometric analysis using Nile Red. Important lesions were also observed in organelles such as mitochondrion, endoplasmic reticulum and Golgi complex. In summary, our study suggests that TC95, an alkyl phosphocholine-trifluralin hybrid molecule, is a promising novel compound against L. amazonensis.
authors.affiliation: Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas, 373, CCS, Ilha do Fundão, Rio de Janeiro 21941-902, Brazil.
authors.forename: Joseane Lima Prado
authors.initials: JL
authors.lastname: Godinho
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Georgikopoulou
authors.forename: Theodora
authors.initials: T
authors.lastname: Calogeropoulou
authors.forename: Wanderley
authors.initials: W
authors.lastname: de Souza
authors.forename: Juliany Cola Fernandes
authors.initials: JC
authors.lastname: Rodrigues
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects; D005434:Flow Cytometry; D006651:Histocytochemistry; D006801:Humans; D002479:Inclusion Bodies / Q000187:drug effects; D020128:Inhibitory Concentration 50; D007894:Leishmania mexicana / Q000166:cytology / Q000187:drug effects* / Q000648:ultrastructure; D016774:Leishmaniasis, Diffuse Cutaneous / Q000469:parasitology; D017737:Macrophages, Peritoneal / Q000187:drug effects; D051379:Mice; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D008857:Microscopy, Interference; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014274:Trifluralin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
chemical_list: C584254:(11-(((2,6-dinitro-4-trifluoromethyl)phenyl)butylamino)(undecylphospinyloxy)ethyl) N,N,N trimethylammonium; D000814:Aniline Compounds; D000981:Antiprotozoal Agents; D010767:Phosphorylcholine; C008625:nitroaniline; D014274:Trifluralin
keywords: Alkyl phospholipid analogues; Chemotherapy; Dinitroanilines; Hybrid molecule; Leishmania; Ultrastructure