title: Microtubule target for new antileishmanial drugs based on ethyl 3-haloacetamidobenzoates.
abstract: A new family of antimicrotubule drugs named (3-haloacetamidobenzoyl) ureas and ethyl 3-haloacetamidobenzoates were found to be cytotoxic to the Leishmania parasite protozoa. While the benzoylureas were shown to strongly inhibit in vitro mammalian brain microtubule assembly, the ethyl ester derivatives were characterized as very poor inhibitors of this process. Ethyl 3-chloroacetamidobenzoate, MF29, was found to be the most efficient drug on the promastigote stage of three Leishmania species (IC50: 0.3-1.8 microM). MF29 maintained its activity against the clinical relevant intracellular stage of L. mexicana with IC50 value of 0.33 microM. It was the only compound that exhibits a high activity on all the Leishmania species tested. This compound appeared to alter parasite microtubule organisation as demonstrated by using antibodies directed against microtubule components and more precisely the class of microtubule decorated by the MAP2-like protein. It is interesting to notice that this MAP2-like protein was identified for the first time in a Leishmania parasite
authors.affiliation: Department of Parasitology and Mycologie médicale, BioCiT UPRES EA 1155, Faculty of Pharmacy, Nantes University, 1 rue Gaston Veil, 44035 Nantes, France.
authors.forename: Abdala
authors.initials: A
authors.lastname: Hiam
authors.forename: David
authors.initials: D
authors.lastname: Sebastien
authors.forename: Bekesi
authors.initials: B
authors.lastname: George
authors.forename: Fellous
authors.initials: F
authors.lastname: Arlette
authors.forename: Jorge
authors.initials: J
authors.lastname: Kalil
authors.forename: Patrice
authors.initials: P
authors.lastname: Le Pape
mesh_terms: D000083:Acetanilides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000469:parasitology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D018314:Leishmania infantum / Q000187:drug effects* / Q000254:growth & development; D018320:Leishmania major / Q000187:drug effects* / Q000254:growth & development; D007894:Leishmania mexicana / Q000187:drug effects* / Q000254:growth & development; D007896:Leishmaniasis / Q000188:drug therapy*; D008099:Liver / Q000187:drug effects / Q000469:parasitology; D008198:Lymph Nodes / Q000187:drug effects / Q000469:parasitology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008855:Microscopy, Electron, Scanning; D008870:Microtubules / Q000187:drug effects*; D021261:Parasitic Sensitivity Tests; D051381:Rats; D012680:Sensitivity and Specificity; D013154:Spleen / Q000187:drug effects / Q000469:parasitology
chemical_list: D000083:Acetanilides; D000981:Antiprotozoal Agents