title: Activity of Fluorine-Containing Analogues of WC-9 and Structurally Related Analogues against Two Intracellular Parasites: Trypanosoma cruzi and Toxoplasma gondii.
abstract: Two obligate intracellular parasites, Trypanosoma cruzi, the agent of Chagas disease, and Toxoplasma gondii, an agent of toxoplasmosis, upregulate the mevalonate pathway of their host cells upon infection, which suggests that this host pathway could be a potential drug target. In this work, a number of compounds structurally related to WC-9 (4-phenoxyphenoxyethyl thiocyanate), a known squalene synthase inhibitor, were designed, synthesized, and evaluated for their effect on T. cruzi and T. gondii growth in tissue culture cells. Two fluorine-containing derivatives, the 3-(3-fluorophenoxy)- and 3-(4-fluorophenoxy)phenoxyethyl thiocyanates, exhibited half-maximal effective concentration (EC50) values of 1.6 and 4.9 μm, respectively, against tachyzoites of T. gondii, whereas they showed similar potency to WC-9 against intracellular T. cruzi (EC50values of 5.4 and 5.7 μm, respectively). In addition, 2-[3- (phenoxy)phenoxyethylthio]ethyl-1,1-bisphosphonate, which is a hybrid inhibitor containing 3-phenoxyphenoxy and bisphosphonate groups, has activity against T. gondii proliferation at sub-micromolar levels (EC50=0.7 μm), which suggests a combined inhibitory effect of the two functional groups.
authors.affiliation: Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EHA, Buenos Aires, Argentina.
authors.forename: María N
authors.initials: MN
authors.lastname: Chao
authors.affiliation: Center for Tropical and Emerging Global Diseases, Department of Cellular Biology, University of Georgia, Athens, GA, 30602, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Li
authors.affiliation: Center for Tropical and Emerging Global Diseases, Department of Cellular Biology, University of Georgia, Athens, GA, 30602, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Storey
authors.affiliation: Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EHA, Buenos Aires, Argentina.
authors.forename: Bruno N
authors.initials: BN
authors.lastname: Falcone
authors.affiliation: Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EHA, Buenos Aires, Argentina.
authors.forename: Sergio H
authors.identifier: 0000-0001-6989-4768
authors.initials: SH
authors.lastname: Szajnman
authors.affiliation: Departamento de Química Orgánica and CIHIDECAR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EHA, Buenos Aires, Argentina.
authors.forename: Sergio M
authors.initials: SM
authors.lastname: Bonesi
authors.affiliation: Center for Tropical and Emerging Global Diseases, Department of Cellular Biology, University of Georgia, Athens, GA, 30602, USA.
authors.forename: Roberto
authors.identifier: 0000-0003-4229-8784
authors.initials: R
authors.lastname: Docampo
authors.affiliation: Center for Tropical and Emerging Global Diseases, Department of Cellular Biology, University of Georgia, Athens, GA, 30602, USA.
authors.forename: Silvia N J
authors.initials: SN
authors.lastname: Moreno
authors.affiliation: Departamento de Química Orgánica and UMYMFOR (CONICET-FCEyN), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EHA, Buenos Aires, Argentina.
authors.forename: Juan B
authors.identifier: 0000-0002-5180-096X
authors.initials: JB
authors.lastname: Rodriguez
mesh_terms: D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry / Q000494:pharmacology; D002522:Chlorocebus aethiops; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D005461:Fluorine / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D010647:Phenyl Ethers / Q000737:chemistry / Q000494:pharmacology*; D012689:Sequence Homology, Nucleic Acid; D013861:Thiocyanates / Q000737:chemistry / Q000494:pharmacology*; D014122:Toxoplasma / Q000187:drug effects*; D014349:Trypanosoma cruzi / Q000187:drug effects*; D014709:Vero Cells
chemical_list: C111921:4-phenoxyphenoxyethyl thiocyanate; D000977:Antiparasitic Agents; D010647:Phenyl Ethers; D013861:Thiocyanates; D005461:Fluorine
keywords: antiprotozoal agents; drug discovery; enzymes; fluorine; inhibitors