Effect of Fluorination on the Structure and Anti-Trypanosoma cruzy

Article pubs.acs.org/IC

Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

Effect of Fluorination on the Structure and Anti-Trypanosoma cruzy Activity of Oxorhenium(V) Complexes with S,N,S‑Tridentate Thiosemicarbazones and Benzoylthioureas. Synthesis and Structures of Technetium(V) Analogues Federico Salsi,† Gisele Bulhões Portapilla,‡ Saskia Simon,† Maximilian Roca Jungfer,† Adelheid Hagenbach,† Seŕ gio de Albuquerque,‡ and Ulrich Abram*,† Downloaded via GUILFORD COLG on July 17, 2019 at 07:18:45 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

†

Institute of Chemistry and Biochemistry, Freie Universität Berlin, Fabeckstrasse 34-36, D-14195 Berlin, Germany Faculdade de Ciencias Farmaceuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Cafe - Vila Monte Alegre, Ribeirão Preto, São Paulo 14040-903, Brazil

‡

S Supporting Information *

ABSTRACT: A series of 16 “3 + 2” mixed-ligand complexes of the general composition [ReO(L1)(L2)] (H2L1a−H2L1d = tridentate thiosemicarbazones having a phenyl group with 4-H, 4-F, 3,5-di-F, and 4-CF3 substituents; HL2a−HL2d = bidentate N,N-diethyl-N′-benzoylthioureas with 4-H, 4-F, 3,5-di-F, and 4CF3 substituents at the benzoyl groups) have been synthesized and characterized by spectroscopic methods and X-ray diffraction. Irrespective of the individual fluorine substitution, the complexes are stable and possess the same general structure. Some systematic electronic effects of the fluorine-substitution patterns of the ligands have been found on the 13C NMR chemical shifts of the N−CN carbon atoms of the {L1}2− and the CO carbon atoms of the {L2}− ligands. Antiparasitic properties of the rhenium complexes have been tested against epimastigotes and trypomastigotes forms of two Trypanosoma cruzi strains and the amastigotes form of one of them. The results of this study indicate that the activity of the rhenium complexes can clearly be modulated by fluorine substitution of their ligands. Some of the fluorinated compounds show a high activity against epimastigotes and trypomastigotes forms of the parasites. Reactions between (NBu4)[TcOCl4] and two representatives of the fluorinated ligands (H2L1b, 4-F-substituted, and H2L1c, 4-CF3-substituted) form stable complexes of the composition [TcOCl(L1b)] and [TcOCl(L1c)]. Subsequent reactions of these products with HL2b (4-F-substituted) give the corresponding [TcO(L1)(L2)] mixed-ligand complexes. Also, the technetium compounds are stable as solids and in solutions and have structures corresponding to those of their rhenium analogues.

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INTRODUCTION

tuning of the biological properties of these complexes by systematic functionalization of the organic ligand requires a huge synthetic effort.11 A mixed-ligand approach gives access to a much more facile and smooth tuning of the ligand properties and, thus, of the biological behavior. “3 + 2” Mixedligand complexes of technetium and rhenium containing tridentate thiosemicarbazonato (tsc2−) and bidentate N,Ndialkyl-N′-benzoylthioureas (R2btu−) ligands (Chart 1b) possess high stability in solution, can readily be prepared, and can be functionalized in an easy and flexible manner with high diversity, avoiding the time-consuming and complicated chemical modification of pentadentate ligands.12,13 Fluorine substitution plays a central role in medicinal chemistry. It is known that the judicious introduction of

Studies about the coordination chemistry of technetium and rhenium are of ongoing interest, not only due to the catalytic activity and interesting photochemical properties of many rhenium compounds,1−4 but also due to the widespread use of 99m Tc in diagnostic nuclear medicine and the potential of the β-emitting radioisotopes 186Re and 188Re in radiotherapy.4−9 In the latter context, there is a continuous need for efficient chelating systems, which afford rapid chelation and stabilization of the radioactive metal under physiological conditions. Ligands that stabilize the {MVO}3+ cores (M = Re, Tc) are of particular interest, since reduction of MO4− ions from commercial generator systems with common reducing agents allows the facile production of oxidometallates(V). Ligand systems, which form stable or highly inert complexes with these cores are, among others, pentadentate N,N-dialkylN′-benzoylthiourea derivatives (Chart 1a).10,11 However, the © XXXX American Chemical Society

Received: April 30, 2019

A

DOI: 10.1021/acs.inorgchem.9b01260 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry Chart 1. (a) MVO Complexes with a Pentadentate Thiocarbamoylbenzamidine10,11 and (b) [3 + 2] MVO Mixed-Ligand Complexes with Thiosemicarbazones and Benzoylthioureas (M = Re, Tc)12,13

needed, in order to build up a theoretical background, which will allow the development of novel diagnostic and/or therapeutic tools in this area. In a previous work, we synthesized a series of fluorinesubstituted thiosemicarbazone and benzoylthiourea derivatives and demonstrated that fluorination strongly influences the biological properties of the uncoordinated compounds themselves. In most cases, fluorination has a positive effect on the selectivity index of the molecules. This means cytotoxicity was reduced and the antiparasitic activity against Trypanosoma cruzy was enhanced.22 On the other hand, the fluorination destabilized some of the molecules in a way that they were more sensitive against hydrolysis. A possible way to enhance both their biological activity and their thermal and hydrolytic stability is, as has recently been published, the use of gold complexes instead of the uncoordinated thiosemicarbazones.23 It might be interesting to see if the formation of Re or Tc complexes also stabilizes the organic compounds and modulates their biological activity. Thus, we synthesized a complete library of rhenium mixed-ligand complexes with fluorinated thiosemicarbazonato and benzoylthioureato ligands (see Chart 2 and Scheme 1) and studied the effect of the

fluorine into an organic molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties.14 Since the approval of the first fluorine-containing drug, the steroid fludrocortisone, by the FDA in 1955, nearly 150 fluorinated molecules have been approved for therapeutic use. In 2010, it was estimated that about 20% of the administered drugs contain fluorine atoms or fluoroalkyl groups, a trend that is increasing from 20% to about 30% for all newly approved drugsexcluding biopharmaceutical products.15 Mostly, fluorine is introduced as a fluoride or trifluoromethyl group in organic molecules, by the substitution of hydrogen, which has a similar size and connectivity, or of hydroxyl or carbonyl groups, which have similar electronegativities.16 Because of the ubiquity of hydrogen in organic molecules, its substitution with fluorine appears particularly suitable for systematic studies. In the last few decades, transition metal complexes have attracted attention in the development of novel drugs, for instance, against cancer and parasitic diseases.17−20 There should be no reason to expect that the positive effects induced by fluorine on the medical properties of organic pharmaceuticals might not be observed for metal complexes as well. Nevertheless, not many studies have been conducted in this field. Chang et al. demonstrated that trifluoromethylation is a useful approach for influencing the pharmacological behavior of Ru(III) anticancer compounds, both by enhancing transport of the molecule in the blood and also by improving cytotoxic activity.21 Furthermore, the addition of trifluoromethyl groups enables 19F NMR studies of ligand exchange processes and protein interactions. The positive effects of fluorination on stability and biodistribution of drugs might also be a powerful tool in inorganic radiopharmacy, in order to influence the biodistribution and the metabolism of a radioactive metal complex in a controlled manner through selective fluorination of its ligand system(s). This, however, is up to now a practically unexplored field. Therefore, systematical studies on the effect of fluorination of the ligands on the structure, coordination properties, and biological activities of Re and Tc complexes are

Chart 2. Thiosemicarbazones and Benzoylthioureas Used Throughout This Paper

different fluorine-substitution patterns on structure, spectroscopic properties, cellular uptake, and antiparasitic activity. Moreover, examples of the corresponding Tc(V) complexes were prepared and structurally characterized in order to Scheme 1. Synthesis of the “3 + 2” Mixed-Ligand Complexes of Rhenium

B


Article

Inorganic Chemistry

Synthesis of the [TcO(L1)(L2)] Complexes. H2L1 (0.1 mmol) was dissolved in 2 mL of CH2Cl2 and added to a solution of (Bu4N)[TcOCl4] (50 mg, 0.1 mmol) in 2.5 mL MeOH. The solution, which immediately turned dark green, was stirred for 2 h, and HL2 (25 mg, 0.1 mmol) in 0.5 mL of CH2Cl2 was added together with 2 drops of Et3N. The resulting dark green solution was stirred for 2 h and then concentrated to about 0.5 mL. The residue was diluted with 3 mL of diethyl ether and filtered through silica gel. The solvent was removed with a stream of dry nitrogen. The crude residue was redissolved in CH2Cl2 (0.5 mL), and MeOH (3 mL) was added. After slow evaporation of the CH2Cl2, the resulting black solid was collected, and the mother liquor was concentrated. The resulting solid residue was redissolved in a minimum amount of CH2Cl2, and EtOH (2 mL) was added. After slow evaporation, more pure product was obtained. Yields and analytical and spectroscopic data of the individual compounds are given in the Supporting Information. Biological Studies. The “3 + 2” mixed-ligand complexes of rhenium have extensively been studied for their biological behavior. In particular, their activities against the epimastigaotes, trypomastigotes, and epimastigotes forms of the parasite T. cruzi have been considered.34−37 Additionally, their cytotoxicity and cellular uptake rates have been determined. Details of the experiments and the related data analyses are described in the Supporting Information.

evaluate in which extent the Re(V) complexes are in this case a reliable model system for Tc(V) complexes.

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EXPERIMENTAL SECTION

Materials. All chemicals and solvents were purchased as reagent grade and used without further purification. Silica gel 230−400 mesh was used. (NBu4)[ReOCl4] and (NBu4)[99TcOCl4] were prepared by standard procedures.24,25 The ligands were prepared according to previously reported methods.22,26 KS13CN was prepared from K13CN (99% isotopic purity) by modification of a literature procedure.27 The product was diluted with nonlabeled potassium thiocyanate to about 10% 13C-enrichment and used without further treatment in the synthesis of the 13C-labeled ligands. Health Precautions. 99Tc is a weak β−-emitter. All manipulations with this isotope were performed in a laboratory approved for the handling of radioactive materials. Normal glassware provides adequate protection against the low-energy β emission of the technetium compounds. Secondary X-rays (bremsstrahlung) play an important role only when larger amounts of 99Tc are used. Physical Measurements. Infrared spectra of the rhenium complexes were measured with a Nicolet iS10 ATR-spectrometer (Thermo Scientific) between 400 and 4000 cm−1. Infrared spectra of 99 Tc complexes were measured as KBr pellets with a Shimadzu FTIR spectrometer between 400 and 4000 cm−1. The intensities of the signals are classified as weak (w), medium (m), and strong (s). UV/ vis spectra were recorded with a SPECORD 40 instrument (Analytik Jena) in a quartz cuvette using methylene chloride as solvent. NMR spectra were recorded with a JEOL 400 MHz multinuclear spectrometer. ESI(+) mass spectra were measured with an Agilent 6210 ESI-TOF (Agilent Technologies). The elemental analyses of carbon, hydrogen, nitrogen, and sulfur were determined using a Heraeus Vario EL elemental analyzer. The 99Tc values were determined by standard liquid scintillation counting. X-ray Crystallography. The intensities for the X-ray determinations were collected on STOE IPDS 2T or Bruker D8 Venture instruments with Mo Kα radiation. The space groups were determined by the detection of systematical absences. Absorption corrections were carried out by SADABS or X-RED32.28−30 Structure solutions were performed with the programs SHELXS 86, SHELXS 97, and SHELXS 2014, and structure refinements were done with the SHELXL 2014 program.31,32 Hydrogen atoms were placed at calculated positions and treated with the “riding model” option of SHELXL. Details about the measurement and refinement data are summarized in the Supporting Information. The representation of molecular structures was done using the program DIAMOND 4.2.2.33 Additional information on the structure determinations is contained in the Supporting Information and has been deposited with the Cambridge Crystallographic Data Centre. Synthesis of the [ReO(L1)(L2)] Complexes. The thiosemicarbazone ligand H2L1 (0.5 mmol) was added to a solution of (Bu4N)[ReOCl4] (0.5 mmol) in MeOH (10 mL) and stirred for 30 min. The deep red mixture was diluted with 60 mL of AcOEt. The organic phase was washed with 3 × 60 mL of brine and dried with MgSO4, and all volatiles were removed in a vacuum. The solid or oily residue was dissolved in CH2Cl2 (2 mL), and the benzoylthiourea ligand HL2 (0.5 mmol) was added in 1 mL of CH2Cl2. Two drops of Et3N were added, and the solution was heated under reflux for 2 h, whereupon the color turned from dark orange-red to dark purple. The solvent was evaporated and the crude residue was recrystallized from boiling alcohol/CHCl3 or from CH2Cl2 by the addition of an alcohol. In both cases, crystals formed slowly by standing at 4 °C overnight. The crystals were isolated by filtration, washed with alcohol, and dried under a vacuum. Synthesis of the [TcOCl(L1)] Complexes. H2L1 (0.1 mmol) in 1 mL CH2Cl2 was added to a solution of (Bu4N)[TcOCl4] (50 mg, 0.1 mmol) in MeOH (2 mL). The solution, which immediately turned dark red, was stirred for 30 min and then concentrated to about 0.3 mL. The resulting black crystals were isolated by decantation and recrystallized from CH2Cl2/EtOH.

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RESULTS AND DISCUSSION “3 + 2” Mixed-ligand oxorhenium(V) complexes with tridentate thiosemicarbazone ligands of type {L1}2− and bidentate N,N-dialkyl/aryl-N′-benzoylthioureato ligands {L2}− can be prepared by reactions of [ReOCl(L1)] complexes with HL2 in good yields or by a direct synthesis starting from (NBu4)[ReOCl4] with an equimolar mixture of H2L1 and HL2 (Scheme 1). For the synthesis of the rhenium complexes with the fluorinated ligands shown in Chart 2, we have chosen the first approach, but without the isolation of the [ReOCl(L1)] complexes, which was not necessary with regard to the almost quantitative yield in the first step, though it proved to be useful to remove the released (NBu4)Cl by extraction with brine before the addition of the benzoylthiourea ligand. Treatment of (NBu4)[ReOCl4] with the ligands H2L1a to H2L1d in methanol leads to the instantaneous formation of red-orange solutions, which reflects the formation of the corresponding [ReOCl(L1)] complexes. Addition of equivalent amounts of HL2 results in a color change to violet. Recrystallization affords deep purple crystalline solids of the composition [ReO(L1)(L2)]. The compounds are soluble in moderately polar solvents such as methylene chloride or chloroform and insoluble in nonpolar solvents and alcohols. We isolated a full library of the 16 mixed-ligand complexes obtained by all possible combinations of the four thiosemicarbazones H2L1 and the four benzoylthiourea HL2 shown in Chart 2. The resulting complexes were fully characterized by elemental analysis, high-resolution mass spectrometry, infrared spectroscopy, and multinuclear NMR. High-resolution ESI+ MS spectra of the complexes show in all cases the signals of the molecular ions as the most intensive signals. Additional signals can be assigned to the cluster ions [M + Na]+ and [M + K]+. Deprotonation of both ligands is indicated by the absence of the NH resonances in the NMR spectra, which appear at about 9 ppm in the spectra of the noncoordinated thiosemicarbazones and at about 8 ppm in those of the benzoylthioureas. The 1H NMR spectra of the [ReO(L1)(L2)] complexes exhibit four sets of signals. The signals of the aromatic protons are located between 8.0 and 6.5 C


Article

Inorganic Chemistry

Table 1. 13C Chemical Shifts (ppm) of the CO Groups of the {L2}− Ligands Depending on the Fluorine-Substitution Patterns

ppm. Their multiplicities and chemical shifts are expectedly affected by the attached fluorine groups. In the region between 4.5 and 3.5 ppm, the signals of the methylene groups are found. The C−NEt2 and C−NMe2 bonds of {L1}2− and {L2}− have partial double bond character, which hinders the free rotation around the bonds. Thus, the protons of the ethyl CH2 groups are nonequivalent and couple with one geminal proton and with the three protons of the adjacent methyl groups, generating a signal with high multiplicity (see graphic reproduction of the spectra in the Supporting Information). The resonances of the NMe2 groups of the {L1}2− ligands appear at about 3 ppm. No hindered rotation is found for these groups. Further structural information can be deduced from 13C NMR spectroscopy. For the unambiguous assignment of all signals, some of the quaternary carbon atoms of the [ReO(L1)(L2)] complexes were labeled with 13C-enriched starting materials. Through selective 13C-labeling of the thiocarbonyl and carbonyl groups of HL2 and of one of the thiocarbonyl groups of H2L1, it is possible to assign unequivocally the corresponding signals. The positions of the remaining quaternary carbon atoms can then be easily identified. Complexation is clearly indicated by a shift of the carbon signals belonging to the inorganic backbone of the ligands. The ReO3+ center seems to donate some electron density to the coordinating CX groups of the organic ligands,38,39 pushing their 13C NMR signals to higher field. In the spectra of the [ReO(L1)(L2)] complexes, the 13C NMR signals appear typically in three regions: the range between 160 and 185 ppm contains the signals of the carbons bonded to the oxygen or sulfur atoms of the ligands, between 125 and 140 ppm appear the resonances of the aromatic rings, and between 40 and 50 ppm the N−CH2 and N−CH3 carbon atoms, while the 13C resonances of the CH3 groups of the ethyl side chains are found between 1.2 and 1.5 ppm. Particularly diagnostic for the characterization of the molecules are the signals in the lowfield spectral range, since these carbon atoms are directly bonded to the donor atoms of the ligands and, thus, most influenced by the coordination of the metal ion. The analysis of their chemical shift might also provide information about the effects of the fluorine substitution on the coordination properties of the ligands. The introduction of fluorine in the periphery of the ligands has generally only weak effects on the chemical shifts of the carbon atoms bearing the donor atoms. For this reason, the spectra of the fluorinated compounds can be easily interpreted by comparison with the model system [ReO(L1a)(L2a)] and by the multiplicity of the signals. The coupling with fluorine gives well-defined and sharp multiplets, which make the assignment in most cases trivial. The chemical shifts of the CS carbon atoms remain unchanged after fluorination, while some shifts are observed for the CO carbon atoms of the benzoylthiourea moieties. The introduction of fluorine atoms or CF3 groups on the ligand {L2}− shifts their signals in almost all cases to higher field. The 19F NMR signals appear in the ranges, where the corresponding signals are found for the uncoordinated thiosemicarbazones or benzoylthioureas,22 and show no systematic shifts in dependence on the second ligand of the mixed-ligand complexes. A remarkable long-range effect is reported with the values in Table 1. While in the absence of fluorine-containing substituents on the phenyl group of {L2}− the fluorination of the thiosemicarbazone moiety has no effect on the 13CO

R2 of HL2 R1 of H2L1

H

4-F

4-CF3

3,5-diF

H 4-F 4-CF3 3,5-diF

170.4 170.3 170.4 170.5

169.5 169.5 168.8 167.8

168.9 169.6 169.0 168.0

171.1 169.6 169.1 168.0

chemical shift, in the presence of fluorine atoms on the aromatic ring of the benzoylthiourea also the fluorination of {L2}2− induces a modulation of the chemical shift of the CO group. A similar effect is observed for the 13C chemical shifts of the NC−N carbon atoms of the ligands {L1}2−. The shielding of the quaternary carbon atoms increases by the substitution of H with F, CF3, and diF in the aromatic ring of the benzoylthiourea. The fluorination of the thiosemicarbazone has no effect when the benzoylthioureato ligand is not substituted (Table 2). Table 2. Dependence of the 13C Chemical Shifts (ppm) of the NC−N Group of {L2}− on the Fluorine-Substitution Patterns

R2 of HL2 1

1

R of H2L

H

4-F

4-CF3

3,5-diF

H 4-F 4-CF3 3,5-diF

164.4 163.7 163.0 161.9

164.3 163.2 163.2 163.3

164.35 163.0 163.1 163.2

164.5 161.8 161.9 161.9

Infrared spectroscopy provides further information. In the nonfluorinated compound [ReO(L1a)(L2a)], the ReO absorption is found at 970 cm−1. The introduction of F or CF3 groups in para position of the phenyl ring has no significant influence on the bonding situation of the terminal oxido ligand. Fluorine atoms in the meta position of {L2}−, however, induce a hypsochromic shift of the ReO vibration, which implies a strengthening of the ReO double bond. Another characteristic signal is the CO stretch of the D


Article

Inorganic Chemistry benzoylthiourea. The introduction of CF3 in the para position or diF in meta positions of {L2}− induces a shift of this band from 1490 to 1500 cm−1. Eleven of the mixed-ligand complexes were characterized by single-crystal X-ray structure analysis. Figure 1 depicts the

Table 3. Re−O1 and Re−O2 Bond Lengths /Å in Relation to the Fluorine-Substitution Pattern (R1, R2)

Re−O1

Re−O2

O1−Re−O2

(H, H) (H, F) (H, diF) (F, H) (CF3, H) (F, F) (F, diF) (CF3, F) (CF3, CF3) (diF, CF3) (diF, diF)

1.686(3) 1.702(2) 1.673(3) 1.652(4) 1.674(3) 1.678(3) 1.667(3) 1.684(2) 1.691(3) 1.682(2) 1.682(3)

2.152(3) 2.184(2) 2.145(3) 2.151(4) 2.224(3) 2.167(3) 2.218(2) 2.204(2) 2.160(3) 2.225(2) 2.209(3)

169.7(1) 169.66(8) 168.9(1) 170.1(2) 174.7(2) 171.0(1) 173.9(1) 172.45(8) 171.2(1) 175.9(1) 177.8(1)

(L2a)] with values of about 0.07 Å. The effects on the other bond lengths are very limited. More remarkable is the effect of fluorination on the coordination geometry. Fluorination of the benzoylthiourea moiety has no significant effect on the bonding situation, but the introduction of a CF3 group on the thiosemicarbazone reduces the bending of the O1−Re−O2 axis, i.e., an increasing of the angle between the two oxygen atoms from 169.7(1) to 174.7(2) is observed. Fluorination has the overall effect of pushing the O−Re−O angles toward the ideal value of 180°. Maximum effects are observed at high degrees of fluorination: (diF, CF3) 175.89° and (diF, diF) 177.89°. The angles in the equatorial plane are not significantly influenced by the fluorination. Exceptions are [ReO(L1b)(L2d)] and [ReO(L1c)(L2b)], where the S(2)−Re−S(3) angles are drastically reduced from 95.24(4)° in [ReO(L1a)(L2a)] to values of 88.00(4)° and 86.77(2)°. The S(1)−Re− S(3) angles increase in these cases to values of 90.57(4) and 93.33(2) with regard to 85.42(4) in [ReO(L1a)(L2a)]. Figure 2 depicts the molecular structure of [ReO(L1d)(L2d)], which has a O1−Re−O2 angle of almost 180°. The mixed-ligand rhenium complexes of this study were evaluated against epimastigotes forms of two T. cruzi strains, Tulahuen LacZ and Y. The antiproliferative activity is given in IC50 values and compared to the reference drug benznidazole (BZ) in Table 4.

Figure 1. Ellipsoid representation of the molecular structure of [ReO(L1a)(L2a)]. Thermal ellipsoids represent 50% probability. Hydrogen atoms have been omitted for the sake of clarity.

molecular structure of the nonfluorinated compound [ReO(L1a)(L2a)] as a reference for this class of molecules. The rhenium atoms have a distorted octahedral coordination environment with the oxido ligand and the oxygen atom of the bidentate ligand {L2}− being in a trans position to each other. The tridentate thiosemicarbazonato ligand {L1}2− occupies three positions in the equatorial plane, which is completed by the sulfur atom of the benzoylthiourea. The Re−O1 distance of 1.686(3) Å is within the normal range for a rhenium−oxygen double bond for this class of compounds.13,40 It has been previously reported that “3 + 2” mixed-ligand complexes with tridentate thiocarbamoylbenzamidines and bidentate benzoylthioureas present notably elongated Re−O bond lengths for the donor oxygen atoms in the trans position to the oxido ligand.13 The Re−O2 bond in [ReO(L1a)(L2a)] is 2.152(3), which is slightly shorter than in the compounds synthesized by da Silva Maia et al.,13 were the lateral chains of the thiosemicarbazide unit were phenyl groups. The different electronic properties of Ph and Et groups also slightly influence the related CS2 and Re−S2 bond lengths. All main structural features discussed for the nonfluorinated complex [ReO(L1a)(L2a)] also apply for the fluorinesubstituted analogues of the present study. A detailed summary of relevant bond lengths and angles of all compounds is given in Table S2 of the Supporting Information. The atomic labeling scheme of Figure 1 also applies for the other members of this series of rhenium complexes. Here, only some structural features shall be discussed, which are correlated with the fluorine substitution of the ligands. This mainly concerns the two Re−O bond lengths and the related angles, which seem to be sensible to the fluorine substitution of the aromatic rings. Table 3 contains the Re−O1 and Re−O2 bond lengths in relation to the respective fluorine substitution. As overall effect for the Re−O single bond, the distance increases under the electronic influence of fluorine. The maximum elongation is observed for compounds [ReO(L1d)(L2c)] and [ReO(L1c)-

Figure 2. Ellipsoid representation of the molecular structure of [ReO(L1d)(L2d)]. Thermal ellipsoids represent 50% probability. Hydrogen atoms have been omitted for the sake of clarity. E


Article

Inorganic Chemistry Table 4. Activity of the Rhenium Complexes in Different T. cruzi Life Stages and Cytotoxicity in Mammalian Cellsa Y strain

compound [ReO(L1a)(L2a)] (1) [ReO(L1a)(L2b)] (2) [ReO(L1a)(L2c)] (3) [ReO(L1a)(L2d)] (4) [ReO(L1b)(L2a)] (5) [ReO(L1c)(L2a)] (6) [ReO(L1d)(L2a)] (7) [ReO(L1b)(L2b)] (8) [ReO(L1b)(L2c)] (9) [ReO(L1b)(L2d)] (10) [ReO(L1c)(L2b)] (11) [ReO(L1c)(L2c)] (12) [ReO(L1c)(L2d)] (13) [ReO(L1d)(L2b)] (14) [ReO(L1d)(L2c)] (15) [ReO(L1d)(L2d)] (16) BZ

Tulahuen lacZ

epimastigotes

epimastigotes

IC50 ± SD

IC50 ± SD

IC50

LLC-MK2 CC50

SI CC50/IC50 amastigotes

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

>100 72.4 36.0 26.3 67.2 >100 83.9 57.3 87.8 30.7 77.4 >100 >100 40.1 72.2 90.5 4.9

>100 >100 >100 >100 >100 88.7 >100 >100 >100 >100 83.5 >100 >100 83.4 >100 91.0 >100

ND >1.4 >2.8 >3.8 >1.5 >0.9 1.2 >1.7 >1.1 >3.3 1.1 ND ND 2.1 >1.4 1.0 >20.44

5.2 4.5 6.4 4.5 4.6 9.8 4.9 4.5 7.7 5.3 9.8 65.3 71.6 5.9 11.3 8.7 15.1

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

1.7 1.1 1.5 0.9 0.7 0.6 0.9 1.1 0.2 0.8 0.1 11.5 12.7 1.4 0.3 2.1 1.3

3.8 3.5 6.5 3.3 3.2 6.2 4.2 3.5 7.2 4.7 7.4 64.6 47.8 4.5 23.7 8.6 17.9

amastigotes

0.7 0.5 1.6 0.7 0.8 0.4 0.2 0.1 1.0 0.9 1.9 21.2 18.7 0.3 7.0 0.2 3.5

Values of concentration are represented in μM. IC50, mean ± SD of three independent experiments. ND, not determined.

a

The mixed-ligand rhenium complexes show a relatively high antiparasitic activity at low concentrations, and most of them are statistically as active as the standard drug benznidazole, except compounds 12 and 13. There are no significant differences of their activity depending on the strains or on the fluorination of compounds. This strongly suggests that the fluorination of the ligands has almost no influence on the antiparasitic activity of the compounds in epimastigotes. On the other hand, there is a tendency of the trifluoromethyl substituent to reduce the biological activity in 6 and 11 and more evident in 12−13, since both exhibit antiepimastigote activity only in high concentrations. Although epimastigotes live in the invertebrate host and they are unable to establish mammalian infection, knowledge about the biological activity of potential drugs in these forms provides information about structure−activity relationships. In addition, many studies have demonstrated that compounds may act similarly in other evolutive forms, such as trypomastigotes.41−44 High levels of trypomastigotes in the bloodstream mark the acute phase in mammalian host; however, they also play an important role during the progression to the chronic Chagas’ disease phase. Those, which are resistant to the immune system, migrate easily to target tissues, where they invade cells and transform into proliferative amastigotes forms.45 Having this in mind, representatives of the rhenium complexes of lower (12), medium (11), and higher activity (4) in epimastigotes were also studied for their activity against the trypomastigotes forms for both strains. The results are visualized in Figure 3. Interestingly, all three compounds show a strong antitrypomastigote activity to Tulahen and Y strains at nanomolar concentrations. Although the activity of compound 12 is somewhat lower (IC50 = 0.54 μM for tulahuen and IC50 = 0.82 μM for Y strains), the influence of the metal ion appears to be a determinant for the biological activity, independent of the fluorinated substituents of the complexes. Similar results have been found by Rodriguez and co-workers, who recently reported that rhenium(I) tricarbonyl complexes with bioactive

Figure 3. Activity of selected rhenium complexes against the trypomastigote forms of Tulahuen and Y strains in comparison to the standard benznidazole (BZ).

thiosemicarbazones also showed a considerable activity against unproliferative forms of the Dm28c strain.46 In the present study, compounds 12, 11, and 4 were 17−46 times more active than benznidazole (BZ) (IC50 = 14.0 ± 1.1 μM) on Y trypomastigotes forms and 26−64 times more active than BZ (IC50 = 14.1 ± 4.6 μM) on Tulahuen strain. T. cruzi strains may respond differently in in vitro and in vivo drugs screening, since it is known that many of them have different profiles of susceptibility to the reference drugs benznidazole and nifurtimox.47 Though trypomastigotes forms have been more sensitive to the rhenium complexes under study, there is no statistical difference in activity between the Tulahuen and Y strains. Benznidazole and nifurtimox are efficient in infection control in vitro, and high cure rates are achieved during an acute-phase treatment. However, they fail dramatically in the chronic phase.48 Recent studies suggest that intracellular amastigote forms play a key role in parasitic persistence and can survive in the mammalian host, hiding in a dormant state inconspicuous F


Article

Inorganic Chemistry to immune response and inactive to standard drugs.49 In this sense, the activity of the rhenium complexes against amastigote forms and cytotoxicity in mammalian cells LCC-MK2 were also investigated. Their trypanocidal activity is given as the IC50 values and compared to BZ (Table 4). The ratio between the cytotoxic activity (CC50) and trypanocidal activity (IC50) is provided in order to determine the selectivity index for the rhenium complexes (SI = CC50/IC50). The selectivity index represents an important parameter to predict possible side effects in preliminary studies in vivo. The compounds should be able to cross the plasma membrane and act on the intracellular organisms without damaging or lysing the host cells. The complexes of this study show low or none cytotoxicity at the highest concentration tested (100 μM), but also a low activity was observed in the amastigotes. Although compounds 4 (IC 50 = 26.5 ± 7.5 μM) and 10 (IC 50 = 30.7 ± 9.2 μM) demonstrate moderate activity on the intracellular forms, the SI value is less than 10, which is frequently used as a recommended criterion for compounds used for drug screening.47 Recent studies have shown that the activity of uncoordinated thiosemicabazones against amastigote forms are strongly influenced by the introduction of fluorine substituents and their position on the molecule.22 As in epimastigotes, the trifluoromethyl group in the compounds 6, 11, 12, and 13 appears to modulate the activity of the rhenium complexes negatively, since they do also show no activity on amastigotes. It should be noted that the nonfluorinated Re complex as well does not show antiamastigote activity at the maximum concentration tested. These results may be explained by a low rate of permeation of the complexes through the cell membrane. Transportation of metal complexes across cell membranes is very complex and still not fully understood.50 In order to gain a deeper understanding of the low activity of the studied complexes in intracellular forms, a cellular uptake assay was performed by ICP-MS, which represents one of the most sensitive methods for the determination of metal or metalloid concentrations in various matrices.51 In this study, infected cell lysates (antiamastigote assay) and uninfected (cytotoxicity) cells were analyzed 72 h after the incubation with the rhenium complexes and the Re concentrations were determined. The results are presented in Table 5 as concentration (μg/L) and percentage of rhenium, calculated from the total amount administered in the wells (17.8 mg/L). Clearly, the detected intracellular rhenium concentrations are very low and less than 5% for all complexes. The Re cell uptake was slightly higher on infected cells, except for compounds 3, 5, 6, and 10. However, regardless of the decrease or increase in the Re uptake, there is a statistically significant difference in the Re uptake between infected and uninfected cells for all fluorinated compounds. It is known that trypomastigotes bind to plasma membrane receptors in the host to trigger the intracellular signaling pathways and the Ca2+ mobilization, which play an important role in membrane invaginations during the T. cruzi invasion.52 Since the uptake of the compounds into the cells may be mediated by more than 400 membrane carriers,50 it is possible that the infected cells may become more susceptible than uninfected cells. Although the data of this study do not show a direct correlation between the fluorination of substituents and the cellular uptake of the complexes, it is evident to link the low

Table 5. Cellular Uptake of the Rhenium Complexes under Cell Culture Conditionsa cell uptake of Re (μg/L) compound [ReO(L1a)(L2a)] (1) [ReO(L1a)(L2b)] (2) [ReO(L1a)(L2c)] (3) [ReO(L1a)(L2d)] (4) [ReO(L1b)(L2a)] (5) [ReO(L1c)(L2a)] (6) [ReO(L1d)(L2a)] (7) [ReO(L1b)(L2b)] (8) [ReO(L1b)(L2c)] (9) [ReO(L1b)(L2d)] (10) [ReO(L1c)(L2b)] (11) [ReO(L1c)(L2c)] (12) [ReO(L1c)(L2d)] (13) [ReO(L1d)(L2b)] (14) [ReO(L1d)(L2c)] (15) [ReO(L1d)(L2d)] (16)

cells 384 308 462 55 206 219 280 184 299 155 323 291 281 308 327 184

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

3 4 3 9 12 6 3 6 4 4 7 3 8 4 7 1

cell uptake of Re (%)

infected cells

cells

infected cells

± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±

2.2 1.7 2.6 3.1 1.2 1.2 1.6 1.0 1.7 0.9 1.8 1.6 1.6 1.7 1.8 1.0

2.2 2.1 2.1 4.3 0.8 0.7 1.6 1.1 1.9 1.1 1.9 2.3 2.1 2.0 2.6 1.0

386 382 380 764 139 117 290 201 341 189 344 405 376 349 457 175

3 15 4 3 4 3 4 5 8 7 5 6 2 3 7 2

a

Mean values and standard deviations (S.D.) from triplicate of 20 points collected for each compound. Significant differences between infected and uninfected cells, ANOVA (p < 0.05).

activity on amastigotes with the low availability of rhenium at the intracellular environment, since most of the complexes show a strong activity on extracellular forms. Corroborating with these findings, complex 4 demonstrates the highest biological activity and highest cellular uptake, even when it is lower than 5%. Another field, where the fluorination of biologically relevant ligand systems have hitherto not found consideration, is the development of metal-containing radiopharmaceuticals. Almost 80% of all routine studies in diagnostic nuclear medicine are done with the metastable nuclear isomer 99mTc, which sums up to 40 million administrations annually. Bearing in mind the strong chemical analogy between the two group 7 metals rhenium and technetium, it shall be interesting to study the related chemistry of technetium. For this reason, we selected the fluorinated ligands H2L1b, H2L1c, and HL2b and synthesized the corresponding complexes [TcOCl(L1b/c)] and the “3 + 2” mixed-ligand species [TcO(L1b)(L2b)] and [TcO(L1c)(L2b] with the long-lived technetium isotope 99Tc and characterized the isolated products (Scheme 2). Scheme 2. Synthesis of the Technetium Complexes

G


Article

Inorganic Chemistry Reactions of (Bu4N)[TcOCl4] with H2L1b or H2L1c form very dark red, almost black solutions. Slow concentration affords black crystals of the complexes [TcOCl(L1b)] and [TcOCl(L1c)]. They were isolated by filtration and characterized by spectroscopic methods, and a single-crystal X-ray structure was determined for [TcOCl(L1b)]. The features of the IR and NMR spectra of [TcOCl(L1b)] and [TcOCl(L1c)] correspond to those that have been discussed for the corresponding rhenium compounds. The TcO bands of the five-coordinate complexes appear in the IR spectra at 959 and 951 cm−1, and the CN stretches, which appear in the spectra of the uncoordinated thiosemicarbazones around 1620 cm−1, are bathochromically shifted by almost 100 cm−1 in the spectra of the complexes. This strongly indicates the formation of chelate rings with a large degree of π-electron delocalization. The absence of IR bands corresponding to NH vibrations and 1H NMR signals belonging to NH protons accounts for the deprotonation of the ligands. The typical splitting of the NMR signals of the ethyl groups due to hindered rotation around the C−N bonds of the ligands is also observed in the spectra of the fluorinated technetium complexes. An ellipsoid representation of the molecular structure of [TcOCl(L1b)] is depicted in Figure 4a. Selected bond lengths and angles are compared to the values in [TcO(L1c)(L2b] in

Table 6. The technetium atom exhibits a distorted squarepyramidal geometry with the oxo ligand in the apical position. Table 6. Selected bond lengths /Å and angles /° in [TcOCl(L1b)] and [TcO(L1c)(L2b] Tc−O1 Tc−S1 Tc−S2 Tc−N3 Tc−Cl/S3 Tc−O2 O1−Tc−S1 O1−Tc−S2 O1−Tc−N3 O1−Tc−Cl/S3 O1−Tc−O2

[TcCl(L1b)]

[TcO(L1c)(2b)]

1.650(2) 2.3053(7) 2.2793(7) 1.996(2) 2.3744(7)

1.650(4) 2.361(2) 2.235(2) 2.026(6) 2.435(2) 2.193(4) 99.1(2) 100.2(2) 103.6(2) 92.0(2) 171.5(2)

112.25(8) 113.23(8) 105.5(1) 105.63(8)

The basal planes are defined by the donor atoms of the tridentate ligand and the chlorido ligand. The bond lengths and angles do not significantly differ from those of the nonfluorinated analogue.38 Reactions of the two [TcOCl(L1)] complexes with HL2b in CH2Cl2 give the mixed-ligand complexes [TcO(L1b)(L2b)] and [TcO(L1c)(L2b)] in good yields. The addition of triethylamine supports the deprotonation of the benzoylthiourea and avoids the presence of HCl in the reaction mixtures, which occasionally leads to undesired decomposition reactions of the organic ligands. The mixed-ligand complexes of technetium can be isolated as dark red, almost black crystals, which are stable as solids and in solution. The IR and NMR spectra of the technetium compounds are very similar to those of the corresponding “3 + 2” complexes of rhenium and shall not separately be discussed here in detail. UV−vis absorption spectra of the two green-brown mixedligand Tc complexes and the related purple Re compounds were measured. All spectra are dominated by very intense charge-transfer bands around 270 nm with large shoulders at ca. 320 nm. Thus, the less intense d−d transitions are almost invisible. The solid state structure of [TcO(L1c)(L2b)] (Figure 4b) is very similar to that of its rhenium analogue, and also in comparison to [TcOCl(L1b)] there are no significant bond length changes obvious (Table 6). The O1−Tc−S/N bond angles, however are smaller in the mixed-ligand complex. This is clearly a consequence of the occupation of the sixth coordination position of the technetium atom by the oxygen atom of the benzoylthioureato ligand. The O1−Tc−O2 angle of 171.5(2)° is also similar to the value in the rhenium compound 11 (172.45(8)°).

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CONCLUSIONS The present study demonstrates that “3 + 2” mixed-ligand complexes of rhenium(V) can be prepared with a variety of fluorinated tridentate thiosemicarbazone and bidentate benzoylthiourea ligands. The synthesis of the complexes is straightforward, and the products are stable as solids and in solution. This is unlike the behavior of the used fluorinated ligands H2L1 and HL2 in their uncoordinated state, where ongoing decompositions have been detected even in the solid state.22 This means that the coordination to metal ions might be an appropriate way to stabilize biologically active

Figure 4. Ellipsoid representations of the molecular structures of (a) [TcOCl(L1b)] and (b) [TcO(L1c)(L2b]. Thermal ellipsoids represent 50% probability. Hydrogen atoms have been omitted for the sake of clarity. H


Article

Inorganic Chemistry

(2) Petersen, A. R.; Fristrup, P. New Motifs in Deoxydehydration: Beyond the Realms of Rhenium. Chem. - Eur. J. 2017, 23, 10235− 10243. (3) Mao, G.; Huang, Q.; Wang, C. Rhenium-Catalyzed Annulation Reactions. Eur. J. Org. Chem. 2017, 2017, 3549−3564. (4) Muller, A. V.; Goncalves, M. R.; Ramos, L. D.; Polo, A. S.; Frin, K. P. M. The importance of the 3MLCT excited state of Ru(II), Re(I) and Ir(III) compounds on development of photosensors, OLEDs and CO2 photoreduction. Quim. Nova 2016, 40, 200−213. (5) Kuntic, V.; Brboric, J.; Vujic, Z.; Uskokovic-Markovic, S. Radioisotopes used as radiotracers for in vitro and in vivo diagnostics. Asian J. Chem. 2016, 28, 235−241. (6) Bartholomä, M. D.; Louie, A. S.; Valliant, J. F.; Zubieta, J. Technetium and gallium derived radiopharmaceuticals: comparing and contrasting the chemistry of two important radiometals for the molecular imaging era. Chem. Rev. 2010, 110, 2903−20. (7) Dilworth, J. R.; Pascu, S. I. The radiopharmaceutical chemistry of technetium and rhenium. In The Chemistry of Molecular Imaging; Long, N., Wong, W.-T., Eds.; Wiley: New York, 2015; pp 137−164. (8) Abram, U.; Alberto, R. Technetium and rhenium - coordination chemistry and nuclear medical applications. J. Braz. Chem. Soc. 2006, 17, 1486−500. (9) Cutler, C. S.; Hennkens, H. M.; Sisay, N.; Huclier-Markai, S.; Jurisson, S. S. Radiometals for Combined Imaging and Therapy. Chem. Rev. 2013, 113, 858−883. (10) Nguyen, H. H.; Pham, C. T.; Abram, U. Rhenium and technetium complexes with pentadentate thiocarbamoylbenzamidines: steps toward bioconjugation. Inorg. Chem. 2015, 54, 5949− 5959. (11) Nguyen, H. H.; Pham, C. T.; Abram, U. Re(V)O and Re(V)NPh complexes with pentadentate benzamidines: Synthesis, structural characterization and DFT evaluation of isomeric complexes. Polyhedron 2015, 99, 216−222. (12) Nguyen, H. H.; Deflon, V. M.; Abram, U. Mixed-ligand complexes of technetium and rhenium with tridentate benzamidines and bidentate benzoylthioureas. Eur. J. Inorg. Chem. 2009, 2009, 3179−3187. (13) da Silva Maia, P. I.; Nguyen, H. H.; Hagenbach, A.; Bergemann, S.; Gust, R.; Deflon, V. M.; Abram, U. Rhenium mixed-ligand complexes with S,N,S-tridentate thiosemicarbazone/thiosemicarbazide ligands. Dalton Trans. 2013, 42, 5111−5121. (14) Gillis, E.-P.; Eastman, K.-J.; Hill, M.-D.; Donnelly, D.-J.; Meanwell, N.-A. Applications of fluorine in medicinal chemistry. J. Med. Chem. 2015, 58, 8315−8359. (15) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J.-L.; Soloshonok, V.-A.; Izawa, K.; Liu, H. Next Generation of fluorinecontaining pharmaceuticals, compounds currently in phase II−III clinical trials of major pharmaceutical companies: new structural trends and therapeutic areas. Chem. Rev. 2016, 116, 422−518. (16) O’Hagan, D. Understanding organofluorine chemistry. An introduction to the C−F bond. Chem. Soc. Rev. 2008, 37, 308−319. (17) Guo, Z.; Sadler, P. J. Metals in medicine. Angew. Chem., Int. Ed. 1999, 38, 1512−1531. (18) Kostova, I. Platinum complexes as anticancer agents. Recent Pat. Anti-Cancer Drug Discovery 2006, 1, 1−22. (19) Thompson, K. H.; Orvig, C. Metal complexes in medicinal chemistry: new vistas and challenges in drug design. Dalton Trans. 2006, 6, 761−764. (20) da Silva Maia, P. I.; Deflon, V. M.; Abram, U. Gold(III) complexes in medicinal chemistry. Future Med. Chem. 2014, 6, 1515− 1536. (21) Chang, S. W.; Lewis, A. R.; Prosser, K. E.; Thompson, J. R.; Gladkikh, M.; Bally, M. B.; Warren, J. J.; Walsby, C. J. CF3 derivatives of the anticancer Ru(III) complexes KP1019, NKP-1339, and their imidazole and pyridine analogues show enhanced lipophilicity, albumin interactions, and cytotoxicity. Inorg. Chem. 2016, 55, 4850−4863. (22) Salsi, F.; Portapilla, G. B.; Schutjajew, K.; Carneiro, Z. A.; Hagenbach, A.; de Albuquerque, S.; da Silva Maia, P. I.; Abram, U.

compounds and promote their transport through cell membranes. Biological tests against epimastigotes and trypomastigotes forms of two T. cruzi strains and an amastigotes form of one of them show that the activity of the compound can clearly be modulated by fluorine substitution of the ligands. A library of 16 compounds with systematic changes of the fluorine substitution has been used in this study. Some of the fluorinated compounds show a high activity against epimastigotes forms of the parasites, which are competitive with the standard drugs benznidazole and nifurtimox. Nevertheless, no clear trend is visible for an optimization of the antiparasitic activity, and more work has to be done in this field. The information derived from the structural part of the present work, namely, that fluorine substitutions in both ligands do not result in drastic changes of the structures of the products or in instable complex molecules, is a good starting point for such ongoing work. With the synthesis and structural characterization of related stable 99Tc complexes, a similar perspective is given for the introduction of fluorine into technetium complexes with potential in diagnostic nuclear medicine.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.9b01260. Analytical and spectroscopic data. Tables containing details about the X-ray structural determinations, selected bond lengths and angles for all rhenium complexes, ellipsoid representations of the molecular structures. 1H, 13C, and 19F NMR spectra of the complexes (PDF) Accession Codes

CCDC 1911807−1911819 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Ulrich Abram: 0000-0002-1747-7927 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was generously supported by the Graduate School (GK 1582) “Fluorine as a key element” of the Deutsche Forschungsgemeinschaft. We also gratefully acknowledge the help of Prof. Fernando Barbosa Júnior and Vanessa Cristina de Oliveira Souza, who performed the cell uptake experiments.

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REFERENCES

(1) Kuramochi, Y.; Ishitani, O.; Ishida, H. Reaction mechanisms of catalytic photochemical CO2 reduction using Re(I) and Ru(II) complexes. Coord. Chem. Rev. 2018, 373, 333−356. I


Article

Inorganic Chemistry Thiosemicarbazones and thiadiazines derived from fluorinated benzoylthioureas: Synthesis, crystal structure and anti-Trypanosoma cruzi activity. J. Fluorine Chem. 2018, 215, 52−61. (23) da Silva Maia, P. I.; Carneiro, Z. A.; Lopes, C. D.; Oliveira, C. G.; Silva, J. S.; de Albuquerque, S.; Hagenbach, A.; Gust, R.; Deflon, V. M.; Abram, U. Organometallic gold(III) complexes with hybrid SNS-donating thiosemicarbazone ligands: cytotoxicity and antiTrypanosoma cruzi activity. Dalton Trans. 2017, 46, 2559−2571. (24) Alberto, R.; Schibli, R.; Egli, A.; Schubiger, P. A.; Herrmann, W. A.; Artus, G.; Abram, U.; Kaden, T. A. Metal carbonyl syntheses XXII. Low pressure carbonylation of [MOCl4]− and [MO4]−: the technetium(I) and rhenium(I) complexes [NEt4]2[MCl3(CO)3]. J. Organomet. Chem. 1995, 493, 119−127. (25) Davison, A.; Trop, H. S.; de Pamphilis, D. V.; Jones, A. G.; Thomas, R. W.; Jurisson, S. S. Tetrabutylammonium Tetrachlorooxotechnetate(V). Inorg. Synth. 2007, 21, 160−162. (26) da Silva Maia, P. I.; Nguyen, H. H.; Ponader, D.; Hagenbach, A.; Bergemann, S.; Gust, R.; Deflon, V. M.; Abram, U. Neutral gold complexes with tridentate SNS thiosemicarbazide ligands. Inorg. Chem. 2012, 51, 1604−1613. (27) Waitkins, G.-R.; Shutt, R. Potassium and sodium selenocyanate. Inorg. Synth. 1946, 2, 186−188. (28) Sheldrick, G. M.; SADABS; Universität of Göttingen: Germany, 2014. (29) X-RED32, A X-ray Data Reduction Tool; STOE & Cie GmbH: Darmstadt, Germany, 2002. (30) Spek, A. L. PLATON: A Multipurpose Crystallographic Tool; Utrecht University: Utrecht, Netherlands, 1980−2014. (31) Sheldrick, G. M. A short history of SHELX. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, 64, 112−122. (32) Sheldrick, G. M. Crystal structure refinement with SHELXL. Acta Crystallogr., Sect. C: Struct. Chem. 2015, 71, 3−8. (33) Brandenburg, K. Diamond-Crystal and Molecular Structure Visualization, version 4.5.1; Crystal Impact GbR: Bonn (Germany), 2018. (34) Rolon, M.; Vega, C.; Escario, J. A.; Gomez-Barrio, A. Development of resazurin microtiter assay for drug sensibility testing of Trypanosoma cruzi epimastigotes. Parasitol. Res. 2006, 99, 103−7. (35) Izumi, E.; Ueda-Nakamura, T.; Veiga, V. F.; Pinto, A. C.; Nakamura, C. V. Terpenes from Copaifera demonstrated in vitro antiparasitic and synergic activity. J. Med. Chem. 2012, 55, 2994− 3001. (36) Buckner, F. S.; Verlinde, C.; LaFlamme, A. C.; vanVoorhis, W. C. Efficient technique for screening drugs for activity against Trypanosoma cruzi using parasites expressing beta-galactosidase. Antimicrob. Agents Chemother. 1996, 40, 2592−2597. (37) Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods 1983, 65, 55−63. (38) Nguyen, H. H.; Maia, P. I. da S.; Deflon, V. M.; Abram, U. Oxotechnetium(V) complexes with a novel class of tridentate thiosemicarbazide ligands. Inorg. Chem. 2009, 48, 25−27. (39) Katritzky, A. R.; Kirichenko, N.; Rogovoy, B. V.; Kister, J.; Tao, H. Synthesis of Mono- and N,N-Disubstituted Thioureas and NAcylthioureas. Synthesis 2004, 2004, 1799−1805. (40) Abram, U. Rhenium. In Comprehensive Coordination Chemistry II; Elsevier, 2003; Vol. 5, pp 271−402. (41) Britta, E. A.; Scariot, D. B.; Falzirolli, H.; Da Silva, C. C.; UedaNakamura, T.; Dias Filho, B. P.; Borsali, R.; Nakamura, C. V. 4Nitrobenzaldehyde thiosemicarbazone: a new compound derived from S-(−)-limonene that induces mitochondrial alterations in epimastigotes and trypomastigotes of Trypanosoma cruzi. Parasitology 2015, 142 (7), 978−988. (42) Meira, C. S.; Guimarães, E. T.; dos Santos, J. A. F.; Moreira, D. R. M.; Nogueira, R. C.; Tomassini, T. C. B.; Ribeiro, I. M.; de Souza, C. V. C.; Ribeiro dos Santos, R.; Soares, M. B. P. In vitro and in vivo antiparasitic activity of Physalis angulata L. concentrated ethanolic extract against Trypanosoma cruzi. Phytomedicine 2015, 22, 969−974.

(43) Beer, M. F.; Frank, F. M.; Germán Elso, O.; Ernesto Bivona, A.; Cerny, N.; Giberti, G.; Luis Malchiodi, E.; Susana Martino, V.; Alonso, M. R.; Patricia Sülsen, V.; Cazorla, S. I. Trypanocidal and leishmanicidal activities of flavonoids isolated from Stevia satureiifolia var. satureiifolia. Pharm. Biol. 2016, 54, 2188−2195. (44) Menna-Barreto, R. F.; Goncalves, R. L.; Costa, E. M.; Silva, R. S.; Pinto, A. V.; Oliveira, M. F.; de Castro, S. L. The effects on Trypanosoma cruzi of novel synthetic naphthoquinones are mediated by mitochondrial dysfunction. Free Radical Biol. Med. 2009, 47, 644− 653. (45) Rassi, A., Jr.; Rassi, A.; Marcondes de Rezende, J. American trypanosomiasis (Chagas disease). Infect Dis Med. Clin. North Am. 2012, 26, 275−291. (46) Rodríguez Arce, E.; Machado, I.; Rodríguez, B.; Lapier, M.; Zúñiga, M.-C.; Maya, J.-D.; Olea Azar, C.; Otero, L.; Gambino, D. Rhenium(I) tricarbonyl compounds of bioactive thiosemicarbazones: Synthesis, characterization and activity against Trypanosoma cruzi. J. Inorg. Biochem. 2017, 170, 125−133. (47) Chatelain, E.; Konar, N. Translational challenges of animal models in Chagas disease drug development: a review. Drug Des., Dev. Ther. 2015, 9, 4807−4823. (48) Morillo, C. A.; Marin-Neto, J. A.; Avezum, A.; Sosa-Estani, S.; Rassi, A., Jr.; Rosas, F.; Villena, E.; Quiroz, R.; Bonilla, R.; Britto, C.; Guhl, F.; Velazquez, E.; Bonilla, L.; Meeks, B.; Rao-Melacini, P.; Pogue, J.; Mattos, A.; Lazdins, J.; Rassi, A.; Connolly, S. J.; Yusuf, S. Randomized Trial of Benznidazole for Chronic Chagas’ Cardiomyopathy. N. Engl. J. Med. 2015, 373, 1295−306. (49) Sanchez-Valdez, F. J.; Padilla, A.; Wang, W.; Orr, D.; Tarleton, R. L. Spontaneous dormancy protects Trypanosoma cruzi during extended drug exposure. eLife 2018, 7, e34039. (50) Spreckelmeyer, S.; Orvig, C.; Casini, A. Cellular transport mechanisms of cytotoxic metallodrugs: an overview beyond cisplatin. Molecules 2014, 19, 15584−610. (51) Puckett, C. A.; Ernst, R. J.; Barton, J. K. Exploring the cellular accumulation of metal complexes. Dalton Trans. 2010, 39, 1159− 1170. (52) Fernandes, M. C.; Andrews, N. W. Host cell invasion by Trypanosoma cruzi: a unique strategy that promotes persistence. Fems. Microbiol. Rev. 2012, 36, 734−747.

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Effect of Fluorination on the Structure and Anti-Trypanosoma cruzy

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