title: Rhenium(I) tricarbonyl compounds of bioactive thiosemicarbazones: Synthesis, characterization and activity against Trypanosoma cruzi.
abstract: American Trypanosomiasis is a chronic infection discovered and described in 1909 by the Brazilian scientist Carlos Chagas. It is caused by the protozoan parasite Trypanosoma cruzi. Although it affects about 10million people in Latin America, the current chemotherapy is still inadequate. The discovery of new drugs is urgently needed. Our group is focused on the development of prospective metal-based drugs mainly based on bioactive ligands and pharmacologically interesting metal ions. In this work three new rhenium(I) tricarbonyl compounds fac-[ReI(CO)3Br(HL)] where HL=5-nitrofuryl containing thiosemicarbazones were synthesized and fully characterized in solution and in the solid state. The in vitro evaluation of the compounds on T. cruzi trypomastigotes (Dm28c strain) showed that the Re(I) compounds are 8 to 15 times more active than the reference drug Nifurtimox and show a 4 to 17 fold increase in activity in respect to the free (HL) ligands. Obtained compounds also show good selectivity indexes (IC50 endothelial cells Ea.hy926/IC50 T. cruzi (Dm28c tripomastigotes)).1H NMR and MS studies, performed with time, showed that the fac-[Re(CO)3Br(HL)] species convert into the dimers [Re2(CO)6(L)2] in solution. Crystal structure of [ReI2(CO)6(L2)2], the product of complexes' dimerization, was solved. Related to the mechanism of action, the studied compounds do not generate radical oxygen species in the parasite (as 5-nitrofuryl derived thiosemicarbazones do) probably due to the unfavorable nitro reduction potential of the generated dimeric species. On the contrary, the compounds produce a decrease of the oxygen consumption rate of the parasites, maybe inhibiting their mitochondrial respiration.
authors.affiliation: Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11800 Montevideo, Uruguay.
authors.forename: Esteban
authors.initials: E
authors.lastname: Rodríguez Arce
authors.affiliation: Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11800 Montevideo, Uruguay.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Machado
authors.affiliation: Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11800 Montevideo, Uruguay.
authors.forename: Belén
authors.initials: B
authors.lastname: Rodríguez
authors.affiliation: ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Michel
authors.initials: M
authors.lastname: Lapier
authors.affiliation: Departamento de Química Inorgánica y Analítica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
authors.forename: María Carolina
authors.initials: MC
authors.lastname: Zúñiga
authors.affiliation: ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Juan Diego
authors.initials: JD
authors.lastname: Maya
authors.affiliation: Departamento de Química Inorgánica y Analítica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
authors.forename: Claudio
authors.initials: C
authors.lastname: Olea Azar
authors.affiliation: Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11800 Montevideo, Uruguay.
authors.forename: Lucía
authors.initials: L
authors.lastname: Otero
authors.affiliation: Química Inorgánica, Facultad de Química, Universidad de la República, Gral. Flores 2124, 11800 Montevideo, Uruguay. Electronic address: dgambino@fq.edu.uy.
authors.forename: Dinorah
authors.initials: D
authors.lastname: Gambino
mesh_terms: D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012211:Rhenium / Q000737:chemistry / Q000494:pharmacology; D013882:Thiosemicarbazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000254:growth & development*
chemical_list: D056831:Coordination Complexes; D013882:Thiosemicarbazones; D014344:Trypanocidal Agents; D012211:Rhenium
keywords: 5-Nitrofuryl derived thiosemicarbazones; Bioactive ligands; Chagas disease; Trypanosoma cruzi; fac-Rhenium(I) tricarbonyl compounds