Microtubule target for new antileishmanial drugs based on ethyl 3-haloacetamidobenzoates |
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| Authors: | Abdala Hiam David Sebastien Bekesi George Fellous Arlette Jorge Kalil Patrice Le Pape |
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| Institution: | 1. Faculty of Pharmacy, Nantes University, Department of Parasitology and Mycologie médicale, BioCiT UPRES EA 1155, 1 rue Gaston Veil, 44035, Nantes, France;2. Laboratory of experimental and clinical Pharmacology, 27 rue Juliette Dodu, 75010, Paris, France;3. Mount Sinai School of Medicine-New York University, Division of Medical Oncology, New York10029, US;4. Facultade de Medicina, Laboratorio de imunologia, USP, Sao Paulo, Brazil |
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| 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 μM). MF29 maintained its activity against the clinical relevant intracellular stage of L. mexicana with IC50 value of 0.33 μM. 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 |
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| Keywords: | Leishmania antileishmanials benzoylureas ethyl 3-haloacetamidobenzoates cytotoxicity microtubule |
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