Heteroleptic Oxidovanadium(V) complexes with activity against infective and non-infective stages of Trypanosoma cruzi

Five heteroleptic compounds, [VVO(IN-2H)(L-H)], where L are 8-hydroxyquinoline derivatives and IN is a Schiff base ligand, were synthesized and characterized in both the solid and solution state. The compounds were evaluated on epimastigotes and trypomastigotes of Trypanosoma cruzi as well as on VERO cells, as a mammalian cell model. Compounds showed activity against trypomastigotes with IC50 values of 0.29–3.02 μM. IN ligand and the new [VVO2(IN-H)] complex showed negligible activity. The most active compound [VVO(IN-2H)(L2-H)], with L2 = 5-chloro-7-iodo-8-hydroxyquinoline, showed good selectivity towards the parasite and was selected to carry out further biological studies. Stability studies suggested a partial decomposition in solution. [VVO(IN-2H)(L2-H)] affects the infection potential of cell-derived trypomastigotes. Low total vanadium uptake by parasites and preferential accumulation in the soluble proteins fraction were determined. A trypanocide effect was observed when incubating epimastigotes with 10 × IC50 values of [VVO(IN-2H)(L2-H)] and the generation of ROS after treatments was suggested. Fluorescence competition measurements with DNA:ethidium bromide adduct showed a moderate DNA interaction of the complexes. In vivo toxicity study on C. elegans model showed no toxicity up to a 100 μM concentration of [VVO(IN-2H)(L2-H)]. This compound could be considered a prospective anti-T. cruzi agent that deserves further research.ANII: POS_NAC_2016_1_129988ANII: POS_NAC_2018_1_15150

Rational drug design of metal complexes for cancer therapy

Funding Information: This work was supported by the Fundação para a Ciência e a Tecnologia, IP/MCTES through national funds—UIDB/00100/2020 (CQE), LA/P/0056/2020 (IMS), UIDP/04378/2020 and UIDB/04378/2020 (UCIBIO), LA/P/0140/2020 (i4HB), and project PTDC/QUI-QIN/0146/2020. TM thanks FCT for Scientific Employment Stimulus (CEECIND) Initiative for the project CEECIND/00630/2017 (acknowledging FCT, as well as POPH and FSE-European Social Fund).publishersversionpublishe

Aromatic amine N-oxide organometallic compounds: Searching for prospective agents against infectious diseases

In search of prospective agents against infectious diseases, 1,1′-bis(diphenylphosphino)ferrocene pyridine-2-thiolato-1-oxide M(II) hexafluorophosphate compounds [M(mpo)(dppf)](PF6), where M = palladium or platinum, were synthesized and fully characterized in the solid state and in solution using experimental and DFT computational techniques. The compounds are isomorphous and the M(II) transition metal ions are in a nearly planar trapezoidal cis-coordination bound to the pyridine-2-thiolato-1-oxide (mpo) and to the 1,1′-bis(diphenylphosphino)ferrocene molecules, both acting as bidentate ligands. Both compounds showed high cytotoxic activity on Trypanosoma cruzi and Mycobacterium tuberculosis (MTB) and acceptable selectivities towards MTB, but good to excellent selectivity index values as anti-T. cruzi compounds. The inclusion of the ferrocene moiety (dppf ligand) improved the selectivity towards the parasite when compared to the previously reported [M(mpo)2] complexes. Related to the probable mechanism of action of the complexes, molecular docking studies on modelled T. cruzi NADH-fumarate reductase (TcFR) predicted that both be very good inhibitors of the enzyme. The effect of the compounds on the enzyme activity was experimentally confirmed using T. cruzi protein extracts. According to all obtained results, both [M(mpo)(dppf)](PF6) compounds could be considered prospective anti-trypanosomal agents that deserve further research.Fil: Rodríguez Arce, Esteban. Universidad de la República; UruguayFil: Mosquillo, M. Florencia. Universidad de la República; UruguayFil: Pérez Díaz, Leticia. Universidad de la República; UruguayFil: Echeverría, Gustavo Alberto. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Piro, Oscar Enrique. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Física; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Merlino, Alicia. Universidad de la República; UruguayFil: Coitiño, E. Laura. Universidad de la República; UruguayFil: Maríngolo Ribeiro, Camila. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Leite, Clarice Q. F.. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Pavan, Fernando R.. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Otero, Lucía. Universidad de la República; UruguayFil: Gambino, Dinorah. Universidad de la República; Urugua

Bioactivity of pyridine-2-thiolato-1-oxide metal complexes: Bi(III), Fe(III) and Ga(III) complexes as potent anti-Mycobacterium tuberculosis prospective agents

In the search for new therapeutic tools against tuberculosis and to further address the therapeutic potential of pyridine-2-thiol 1-oxide (Hmpo) metal complexes, two new octahedral [M(III)(mpo)3] complexes, with M = Ga or Bi, were synthesized and characterized in the solid state and in solution. Attempts to crystallize [Ga(III)(mpo)3] in CH2Cl2 led to single crystals of the reaction product [GaCl(mpo)2], where the gallium(III) ion is in a square basis pyramidal environment, trans-coordinated at the basis to two pyridine-2-thiolato 1-oxide anions acting as bidentate ligands through their oxygen and sulfur atoms. The biological activity of the new [M(III)(mpo)3] complexes together with that of the previously reported Fe(III) analogous compound and the pyridine-2-thiol 1-oxide sodium salt (Na mpo) was evaluated on Mycobacterium tuberculosis. The compounds showed excellent activity, both in the standard strain H37Rv ATCC 27294 (pan-susceptible) and in five clinical isolates that are resistant to the standard first-line anti-tuberculosis drugs isoniazid and rifampicin. These pyridine-2-thiol 1-oxide derivatives are promising compounds for the treatment of resistant tuberculosis.Instituto de Física La Plat

New heterobimetallic ferrocenyl derivatives are promising antitrypanosomal agents

In the search for a more effective chemotherapy for the treatment of Chagas´ disease and human African trypanosomiasis, caused by Trypanosoma cruzi and Trypanosoma brucei parasites, respectively, the use of organometallic compounds may be a promising strategy. In this work, eight new heterobimetallic compounds are described including four 5-nitrofuryl containing thiosemicarbazones as bioactive ligands (HL1-HL4) and dppf = 1,1′-bis(diphenylphosphino) ferrocene as an organometallic co-ligand. Complexes of the formula [MII(L)(dppf)](PF6) with M = Pd or Pt were synthesized and fully characterized in the solid state and in solution, including the determination of the molecular structure of four of them by single crystal X-ray diffraction methods. Most compounds showed activity in the low micromolar or submicromolar range against both parasites, with the platinum compounds being more active than the palladium analogues. Activity was significantly increased by generation of the M-dppf compounds (3-24 fold increase with respect to free ligands HL for T. cruzi and up to 99 fold increase with respect to HL for T. brucei). The inclusion of the organometallic co-ligand also led to lower toxicity in mammalian cells and higher selectivity towards both parasites when compared to the free HL compounds. The complexes interact with DNA and affect the redox metabolism of the parasites. Furthermore, the most active and selective compound of the new series showed no in vivo toxicity in zebrafish embryos.Fil: Rodríguez Arce, Esteban. Universidad de la República; UruguayFil: Putzu, Eugenia. Universidad de la República; UruguayFil: Lapier, Michel. Universidad de Chile; ChileFil: Maya, Juan Diego. Universidad de Chile; ChileFil: Olea Azar, Claudio. Universidad de Chile; ChileFil: Echeverría, Gustavo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Piro, Oscar Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Medeiros, Andrea. Instituto Pasteur de Montevideo; Uruguay. Universidad de la República; UruguayFil: Sardi, Florencia. Instituto Pasteur de Montevideo; UruguayFil: Comini, Marcelo. Instituto Pasteur de Montevideo; UruguayFil: Risi, Gastón. Instituto Pasteur de Montevideo; UruguayFil: Salinas, Gustavo. Instituto Pasteur de Montevideo; UruguayFil: Abad Villamor, Ana Isabel. Instituto Superior Técnico; PortugalFil: Pessoa, João Costa. Instituto Superior Técnico; PortugalFil: Otero, Lucía. Universidad de la República; UruguayFil: Gambino, Dinorah. Universidad de la República; Urugua

Risedronate metal complexes potentially active against Chagas disease

In the search for new metal-based drugs for the treatment of Chagas disease, the most widespread Latin American parasitic disease, novel complexes of the bioactive ligand risedronate (Ris, (1-hydroxy-1-phosphono-2-pyridin-3-yl-ethyl)phosphonate), [MII(Ris)₂]·4H₂O, where M═Cu, Co, Mn and Ni, and [NiII(Ris)₂(H₂O)2]·H₂O were synthesized and characterized by using analytical measurements, thermogravimetric analyses, cyclic voltammetry and infrared and Raman spectroscopies. Crystal structures of [CuII(Ris)₂]·4H₂O and [NiII(Ris)₂(H₂O)₂]·H₂O were solved by single crystal X-ray diffraction methods. The complexes, as well as the free ligand, were evaluated in vitro against epimastigotes and intracellular amastigotes of the parasite Trypanosoma cruzi, causative agent of Chagas disease. Results demonstrated that the coordination of risedronate to different metal ions improved the antiproliferative effect against T. cruzi, exhibiting growth inhibition values against the intracellular amastigotes ranging the low micromolar levels. In addition, this strong activity could be related to high inhibition of farnesyl diphosphate synthase enzyme. On the other hand, protein interaction studies showed that all the complexes strongly interact with albumin thus providing a suitable means of transporting them to tissues in vivo.Centro de Química Inorgánic

Research of new mixed-chelate copper complexes with Quinoxaline N1,N4-dioxide derivatives and Alanine as ligands, potential antimycobacterial agents

Three new mixed-chelate copper complexes with 3-aminoquinoxaline-2-carbonitrile N1,N4-dioxide derivatives and alanine as ligands were synthesized in solid state. The spectroscopic characterization (FTIR, EPR, UV-Vis) showed that copper coordinated through the amine and the N-oxide groups of the quinoxaline derivatives and the amine and carboxylate moieties from alanine forming a dimeric species. The tree complexes showed in vitro activity against M. tuberculosis H37Rv (ATCC 27294) similar to that of ethambutol while they are inactive against E. coli and S. aureus.Tres nuevos complejos mixtos de cobre con derivados de 3-aminoquinoxalina-2-carbonitrilo N1,N4-dióxido y alanina como ligandos fueron sintetizados en estado sólido. La caracterización espectroscópica (FTIR, EPR, UV-Vis) mostró que el Cu coordina con el grupo amino y el N-óxido del derivado quinoxalínico y con el amino y el carboxilato de la alanina formando especies diméricas. Los tres complejos mostraron actividad frente al M. tuberculosis H37Rv (ATCC 27294) similar a la del etambutol, mientras que fueron inactivos frente a E. coli y S. aureus.PEDECIB

New copper-based complexes with quinoxaline 'N POT.1', 'N POT.4'-dioxide derivatives, potential antitumoral agents

Taking into account our previous studies on cytotoxic metal compounds, new copper complexes with 3-aminoquinoxaline-2-carbonitrile N1,N4-dioxide derivatives as ligands were synthesized and characterized by different spectroscopic methods. The hypoxic selective cytotoxicity towards V79 cells and the superoxide dismutase-like activity of the complexes were determined and related to physicochemical properties of the compounds. In particular, the copper(II) complex with 3-amino-6-chloro-7-fluoroquinoxaline-2-carbonitrile N1,N4-dioxide showed cytotoxic selectivity in hypoxia being the most lipophilic compound of the series. On the contrary, the complex with 3-aminoquinoxaline-2-carbonitrile N1,N4-dioxide was cytotoxic but not selective and that with 3-amino-7-chloro-6-methoxy-quinoxaline-2-carbonitrile N1,N4-dioxide was not cytotoxic towards V79 cells neither in oxia nor in hypoxia in the assayed conditions. The σm Hammett substituent electronic descriptor was related to the effect in hypoxic conditions and the SOD-like activity was correlated to the effect in normoxia.Comisión Honoraria de Lucha Contra el Cáncer (CHLCC)Comisión Sectorial de Investigación Científica (CSIC)PEDECIB

Design of novel iron compounds as potential therapeutic agents against tuberculosis

In the search for new therapeutic tools against tuberculosis two novel iron complexes, [Fe(L–H)3], with 3-\ud aminoquinoxaline-2-carbonitrile N1,N4-dioxide derivatives (L) as ligands, were synthesized, characterized by\ud a combination of techniques, and in vitro evaluated. Results were compared with those previously reported\ud for two analogous iron complexes of other ligands of the same family of quinoxaline derivatives. In addition,\ud the complexes were studied by cyclic voltammetry and EPR spectroscopy. Cyclic voltammograms of the iron\ud compounds showed several cathodic processes which were attributed to the reduction of the metal center\ud (Fe(III)/Fe(II)) and the coordinated ligand. EPR signals were characteristic of magnetically isolated high-spin\ud Fe(III) in a rhombic environment and arise from transitions between mS=±1/2 (geff~9) or mS=±3/2\ud (geff~4.3) states. Mössbauer experiments showed hyperfine parameters that are typical of high-spin Fe(III)\ud ions in a not too distorted environment. The novel complexes showed in vitro growth inhibitory activity on\ud Mycobacterium tuberculosis H37Rv (ATCC 27294), together with very low unspecific cytotoxicity on\ud eukaryotic cells (cultured murine cell line J774). Both complexes showed higher inhibitory effects on M.\ud tuberculosis than the “second-line” therapeutic drugs.CYTEDPEDECIBA Químic