This work describes the synthesis and characterization of organometallic N-acylhydrazones (NAHs) of general formula R1-C(O)-NH-NC(R2)(4- or 5-nitrothienyl) (4a,b-7a,b), where R1 = ferrocenyl (a) or cyrhetrenyl (b) and R2 = H or Me. The X-ray crystal structures of 4b, 5a, 5b, and 6b are described. UV-Vis studies confirmed that the compounds remained stable in DMSO/buffer mixtures for 24 h. In vitro studies of the biological activities of 4a,b-7a,b against Trypanosoma cruzi (T. cruzi) and Trypanosoma brucei (T. brucei) showed that the organometallic derivatives were more active against T. brucei (EC50 = 0.18-12.9 μM) than against T. cruzi (EC50 = 4.24-78.8 μM). Except for 5b, cyrhetrenyl derivatives were more potent than their ferrocenyl analogs, showing up to a 7-fold increase in antiparasitic activity. In all cases, the 5-nitrothiophene derivatives (6a,b-7a,b) also outperformed their 4-nitro analogs (4a,b-5a,b), underscoring the strong impact of nitro-group positioning on biological activity. Compound 6b proved to be the most promising anti-T. brucei agent due to its potency (EC50 = 0.47 μM) and selectivity (SI = 110). Comparison of data for 6a and 6b and their isomers 8a and 8b [R1-C(H)N-NH-C(O)(5-nitrothienyl)] revealed that antiparasitic activity and cytotoxicity are strongly influenced by the position of the acylhydrazone group linking the organometallic fragment and the nitroheterocycle. Evaluation of T. brucei susceptibility showed that the 5-nitro derivatives undergo Type I nitroreductase-dependent activation (-tet/+tet ratios: 4.2-5.6), while the 4-nitro counterparts exhibited only minor shifts (1.5-2.0). These results indicate that small structural modifications in NAHs can significantly affect their antiparasitic properties.

A new series of organometallic 1,2,3-triazoles with the general formula [(eta 5-C5H4-(1)-1,2,3-triazole-(4)-R)MLn], where MLn = Fe(eta 5-C5H5), with R = acetyl (1a), methyl-N-Boc (2a); and MLn = Re(CO)s, with R = acetyl (1b), methyl-N-Boc (2b), were obtained in good yields using the copper(I)-catalyzed azide-alkyne cycloaddition reaction of the corresponding organometallic azides (P1 or P2) with 3-butyn-2-one or N-Boc-propargylamine. All compounds were characterized by conventional spectroscopic and analytical techniques (infrared and 1H and 13C NMR spectroscopy, and elemental analysis). The proposed molecular structures of 1b, 2a, and 2b were confirmed via single-crystal X-ray diffraction. To evaluate the potential anti-inflammatory properties, all complexes were tested in vitro against 5-hLOX, COX-1, COX-2, and 15-sLOX. Among them, only complex 1b showed modest activity against COX-1 (84.8 & micro;M) and COX-2 (100.1 & micro;M), suggesting that these structural features could be useful for designing related systems.

In the search for new organometallic compounds that can be used as anti-inflammatory agents, the novel 2-hydroxy-benzylidene-cymanthrenyl-sulfonylhydrazone ligand [(eta Luo et al. (2022)5-C5H4S (O)2NH-N=CH-C6H4-2-OH)Mn(CO)3] (HL) and its palladium(II) (1a), nickel(II) (1b), and copper(II) (1c) complexes were synthesized. All compounds were characterized using conventional spectroscopic and analytical techniques (infrared and 1H and 13C NMR spectroscopy, mass spectrometry, and elemental analysis). The proposed molecular structures of HL, 1b, and 1c were confirmed via single-crystal X-ray diffraction. The inhibition of enzymes LOX and COX-2, which are associated with inflammation, by the new ligand and its metal complexes was studied. Our findings revealed that COX-2 was inhibited by the precursor [(eta Luo et al. (2022)5-C5H4S (O)2NH-NH2)Mn(CO)3] (p2) (23.6 mu M) and complex 1a (15.9 mu M), indicating high inhibitory potency. This study provides the first evidence of this type of complex functioning as a COX-2 inhibitor. Additionally, docking studies showed that the most significant interactions between COX-2 and the most potent inhibitors occurred through two key residues in the enzyme: Tyr385 and Tyr355.

In search of new organometallic-1,2,3-triazoles, this work describes a convenient synthesis to obtain ferrocenyl and cyrhetrenyl 1,2,3-triazole derivatives containing aminomethyl fragment. On this regard, the compounds of general formulae [(g5-C5H4-(1)-1,2,3-triazole-(4)-CH2NH2)MLn] [where MLn =Fe(eta(5)-C5H5) (1a), Re(CO)3 (1b)] were obtained via tert-butoxycarbonyl (BOC) deprotection under acid conditions of the corresponding protected triazoles [(eta(5)-C5H4-(1)-1,2,3-triazole-(4)-CH2NH(C=O)OC(CH3)3)MLn] with MLn = Fe(eta(5)-C5H5) (P1), Re(CO)3 (P2)], with good yields (89-95%). In addition, the reactivity of aminomethyl compounds (1a-b) was evaluated in condensation reactions with 4-(1H-1,2,4-triazol-1-yl)benzaldehyde, isolated the Schiff bases [(eta(5)-C5H4-(1)-1,2,3-triazole-(4)-CH2N=CH-(1)-C6H4-(4)-1H-1,2,4-triazole)MLn] (2a-b) [where MLn =Fe(eta(5)-C5H5) (2a), Re(CO)3 (2b)] under mild reactions conditions. All compounds were characterized by FT-IR, 1H NMR spectroscopy and elemental analysis. Moreover, the molecular structure of 2a was determined by single-crystal X-ray diffraction.

A homo- and a hetero-dinuclear organometallic complex, [(Cp)Fe(Cp)-CH(Tz)-(Cp)M(Cp)] (M = Fe (3a), Ru (3b); Cp- = cyclopentadienyl, Tz = 1,2,4-triazole), were prepared from carbinol precursors [(Cp)Fe(Cp)-CH(OH)(Cp)M(Cp)] (M = Fe (2a), Ru (2b), and 1,2,4-triazole. Complexes 3a-b were characterized by 1H and 13C NMR spectroscopy, mass spectrometry (MS), and elemental analysis. The X-ray crystal structure of 3a reveals two ferrocenyl units, whereas 3b exhibits two Fe/Ru mixed-occupancy metal sites in a 1:1 ratio, along with disorder in the pendant Cp units in both structures. These findings are consistent with the MS data, which clearly show the [M]+ ion for 3a (Fe/Fe) and 3b (Fe/Ru), but no Fe/Fe or Ru/Ru species for 3b. The antiproliferative activities of 3a and 3b were evaluated against HeLa, MCF-7, and HT-29 cancer cell lines, with IC50 values ranging from 14 to 95 mu M. For comparison, cisplatin exhibited IC50 values between 0.33 and 22 mu M under the same conditions.

Two new metallocene complexes with formulation [Fe(eta 5-C5H5){(eta 5-C5H4)-N--CH-2-C4H2O-(5-C6H4-2-NO2)}] (3) and [Fe(eta 5-C5H5){(eta 5-C5H4)-N--CH-2-C4H2O-(5-C6H4-4-NO2)}] (4) have been synthesized and their antitrypanosomal activity has been evaluated. Complexes 3 and 4 were obtained by condensation reaction of ferrocenylamine (1) with respective 5-(2-nitrophenyl)-2-furancarboxaldehyde (2a) or 5-(4-nitrophenyl)-2furancarboxaldehyde (2b). The complexes were fully characterized by spectroscopic techniques (FT-IR, 1H and 13C{1H} NMR, and HRMS), which confirm their correct obtainment. The crystal structures of 3 and 4 were also determined by single crystal X-ray diffraction. Furthermore, UV-visible studies revealed that compounds 3 and 4 exhibited suitable stability in DMSO:HEPES buffer solution (80:20) throughout 24 h. The in vitro antiparasitic activities of ferrocenyl imine derivatives 3 and 4 were assessed against two species of parasites, Trypanosoma cruzi (T. cruzi) and Trypanosoma brucei (T. brucei). The obtained results revealed that compound 3 (EC50 = 0.44 mu M) exhibited nearly a 40 -fold greater efficacy as an anti -T. brucei agent compared to derivative 4 (EC50 = 16.0 mu M). Moreover, compound 3 demonstrated superior potency when compared with its organometallic analogs (EC50 = 2.42-13.3 mu M), which were previously reported by our research group. Interestingly, the EC50 value of 3 was found to be 8 times greater than that of nifurtimox (EC50 = 3.56 mu M). The cytotoxicity of the ferrocenyl imines was also evaluated on the L6 rat skeletal myoblast cell line.

In the search of new cymantrenyl- and ferrocenyl-sulfonamides as potencial inhibitors of human carbonic anhydrases (hCAs), four compounds based on N-ethyl or N-methyl benzenesulfonamide units have been obtained. These cymantrenyl (1a-b) and ferrocenyl (2a-b) derivatives were prepared by the reaction between aminobenzene sulfonamides ([NH2-(CH2)n-(C6H4)-SO2-NH2)], where n = 1, 2) with cymantrenyl sulfonyl chloride (P1) or ferrocenyl sulfonyl chloride (P2), respectively. All compounds were characterized by conventional spectroscopic techniques and cyclic voltammetry. In the solid state, the molecular structures of compounds 1a, 1b, and 2b were determined by single-crystal X-ray diffraction. Biological evaluation as carbonic anhydrases inhibitors were carried out and showed derivatives 1b y 2b present a higher inhibition than the drug control for the Human Carbonic Anhydrase (hCA) II and IX isoforms (KI = 7.3 nM and 5.8 nM, respectively) and behave as selective inhibition for hCA II isoform. Finally, the docking studies confirmed they share the same binding site and interactions as the known inhibitors acetazolamide (AAZ) and agree with biological studies.

In the search of new organometallic precursors, this contribution describes a convenient synthesis to obtain new ferrocene-based sulfonyl diamine derivatives. The [(η5-C5H4SO2NH-CH2-CH2-NH2)Fe(η5-C5H5)] (1) and [(η5-C5H4SO2NH-C6H4-NH2)Fe(η5-C5H5)] (2) compounds were prepared by the reaction between (η5-C5H4SO2Cl)Fe(η5-C5H5) and the respective diamine precursor: ethylenediamine (1) or p-phenylenediamine (2) in good yields (86% for 1; 70% for 2). Both compounds were characterized by conventional spectroscopic techniques (infrared spectroscopy, nuclear magnetic resonance spectroscopy, mass spectrometry and elemental analysis) and cyclic voltammetry. In addition, the molecular structure of 1 was determined by single-crystal X-ray diffraction.

A series of new ferrocenyl nitroheterocyclic sulfonylhydrazones (1a–4a and 1b–2b) were prepared by the reaction between formyl (R = H) or acetyl (R = CH3) nitroheterocyclic precursors [4/5-NO2(C5H2XCOR), where X = O, S)] and ferrocenyl tosyl hydrazine [(η5-C5H5)Fe(η5-C5H4SO2-NH-NH2)]. All compounds were characterized by conventional spectroscopic techniques. In the solid state, the molecular structures of compounds 1a, 2b, and 3a were determined by single-crystal X–ray diffraction. The compounds showed an E-configuration around the C=N moiety. Evaluation of trypanocidal activity, measured in vitro against the Trypanosoma cruzi and Trypanosoma brucei strains, indicated that all organometallic tosyl hydrazones displayed activity against both parasite species with a higher level of potency toward T. brucei than T. cruzi. Moreover, the biological evaluation showed that the 5-nitroheterocyclic derivatives were more efficient trypanocidal agents than their 4-nitroheterocyclic counterparts.

In the search of new bioorganometallic compounds as potential inhibitors of human (h) carbonic anhydrases (hCAs, EC 4.2.1.1), heterobinuclear ruthenium(II) complexes based on organometallic-acylhydrazones have been obtained. The complexes (1a-b, 2a-b) were prepared by reaction between the corresponding organometallic-acylhydrazone of the general formula [{(eta(5)-C5H4)CH=N-NH-C(O)-C6H4-4-SO2NH2}]MLn or [{(eta(5)-C5H4) CH=N-NH-C(O)-CH2CH2-NH-C6H4-4-SO2NH2}]MLn (where MLn = Re(CO)(3); FeCp) and [Ru(p-cymene)Cl-2](2). All compounds were characterized by conventional spectroscopic techniques and cyclic voltammetry. Biological evaluation as CA inhibitors (CAIs) was carried out and showed derivatives 1a, 2a and 2b to behave as selective inhibition against the tumors associate isoforms hCA IX and XII making them interesting candidates for pre-clinical evaluation in various hypoxic tumors in which the two enzymes are overexpressed.

The dissymmetrical and dipolar Y(III) complex 2 and its cationic precursor 1, containing the proligands 5,10,15,20-tetrakis(4-bromophenyl)porphyrin L1 and 1-anisyl-1,3-butanedione L2, were synthesized at fairly high yields, ranging from 40 to 78%, by conventional and microwave-assisted techniques, and were isolated as a microcrystalline compound. The products obtained in each case were characterized by 1H-NMR, mass spectrometry, elemental analysis, Med-IR and Far-IR. The IR information collected shows good agreement with respect to the density functional theory (DFT) calculations carried out, validating the molecular geometry in each case. This innovative one-pot microwave-based method contributes an efficient pathway for obtaining challenging molecular architectures based on monoporphyrinate complexes without Diglyme.

This study compares the nitro group position of thienyl imines bound to organometallic fragments, and the respective electrochemical and anti-parasitic properties. Ferrocenyl and cyrhetrenyl imines derived from 4-nitrothiophene (1a-3a) and 5-nitrothiophene (1b-3b) were synthesized and characterized by spectroscopic techniques. In addition, molecular structure of 1a, 2a and 3a were determined by X-ray crystallography. The reduction potential of the nitro group (E-1/2), determined by cyclic voltammetry, shows that imines with a 5-nitrothiophene moiety exhibit lower E-1/2 values (E-1/2 = -0.56 to -0.78 V) than 4-nitro derivatives (E-1/2 = -0.92 to -1.04 V), indicating that 5-nitro compounds better generate radical species. The 5-nitrothiophene derivatives (1b-3b) were more active against T. b. brucei (trypomastigotes) and T. cruzi (epimastigotes) than 4-nitrothiophene analogues (1a-3a). Enhanced trypanocidal properties in 5-nitrothiophenes may be due to NO2 group reduction being readily converted to their downstream, trypanocidal products. Based on the anti-parasitic activity and Selectivity Index determined for all derivatives, 1b emerged as an appropriated agent for treatment of trypanosomal infections. Additionally, evaluations of T. b. brucei susceptibility showed that compound 3b is a substrate for TbNTR1. Density Functional Theory (DFT) calculations were used as an approximation to rationalize the influence of nitro group positions on the heterocyclic ring regarding electrochemical behaviour and anti-parasitic activity. (C) 2020 Elsevier Ltd. All rights reserved.

Four N-acylhydrazones of general formulae [R1-C(O)-NH-N=C(R2)(5-nitrofuryl)] with (R1 = ferrocenyl or cyrhetrenyl and R2 = H or Me) are synthesized and characterized in solution and in the solid-state. Comparative studies of their stability in solution under different experimental conditions and their electrochemical properties are reported. NMR studies reveal that the four compounds are stable in DMSO-d6 and complementary UV-Vis studies confirm that they also exhibit high stability in mixtures DMSO:H2O at 37 C. Electrochemical studies show that the half-wave potential of the nitro group of the N-acylhydrazones is smaller than that of the standard drug nifurtimox and the reduction process follows a self-protonation mechanism. In vitro studies on the antiparasitic activities of the four complexes and the nifurtimox against Trypanosoma cruzi and Trypanosoma brucei reveal that: i) the N-acylhydrazones have a potent inhibitory growth activity against both parasites [EC50 in the low micromolar (in T. cruzi) or even in the nanomolar (in T. brucei) range] and ii) cyrhetrenyl derivatives are more effective than their ferrocenyl analogs. Parallel studies on the L6 rat skeletal myoblast cell line have also been conducted, and the selectivity indexes determined. Three of the four N-acylhydrazones showed higher selectivity towards T. brucei than the standard drug nifurtimox. Additional studies suggest that the organometallic compounds are bioactivated by type I nitroreductase enzymes.

Three complexes of the general formula M{CpFe(η5‐C5H4CH=N–N=C(S)NH2}2 [where M = NiII (2a), PdII (2b) and ZnII (2c)] were synthesized with formylferrocene thiosemicarbazone (1) as a bidentate ligand. All compounds were characterized using conventional spectroscopic and analytical techniques (infrared, 1H and 13C NMR, mass spectrometry and elemental analysis). The molecular structure of 2b was confirmed by single‐crystal X‐ray analysis. To study the photocatalytic activity of the new complexes (2a–c), methylene blue (MB) was selected as a model pollutant. After 180 min, the degradation efficiency of MB reached 87% for 2a, 76% for 2b and 85% for 2c, and all complexes showed a higher photocatalytic activity than the formylferrocene thiosemicarbazone free ligand 1. Theoretical studies were used to characterize the geometry and electronic structure of the compounds and to provide a rational explanation for the measured photocatalytic activity.

A series of bio-organometallic-hydrazones of the general formula [{(eta(5)-C5H4)-C(R)=N-N(H)-C6H4-4-SO2NH2}]MLn(MLn = Re(CO)(3), Mn(CO)(3), FeCp; R=H, CH3) were prepared by reaction of formyl/acetyl organometallic precursors with 4-hydrazino-benzenesulphonamide. All compounds were characterized by conventional spectroscopic techniques (infra-red, H-1 and C-13 NMR, mass spectrometry and elemental analysis). Biological evaluation as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors agents was carried out using four human/h) isoforms, hCA I, II, IX and XII. The cytosolic isoforms hCA I and II were effectively inhibited by almost all derivatives with inhibition constants of 1.7-22.4 nM. Similar effects were observed for the tumour-associated transmembrane isoform hCA XII (K(I)s of 1.9-24.4 nM). hCA IX was less sensitive to inhibition with these compounds. The presence of bio-organometallic or metallo-carbonyl moieties in the molecules of these CAIs makes them amenable for interesting pharmacologic applications, for example for compounds with CO donating properties.

The bioorganometallic compounds 2-cyrhetrenyl-5-nitro-benzimidazole (Bzn-1) and 2-ferrocenyl-5-nitro-benzimidazole (Bzn-2) have been proposed as potential anti-Trypanosoma cruzi agents. On this regard, electrochemical, electron spin resonance and biological studies were carried out. Cyclic voltammetry experiments showed the generation of nitro anion radical derivatives and a self-protonation process was observed. Nitro anion radicals generated were characterized and analyzed using electron spin resonance spectroscopy. The compounds were tested in vitro against Trypanosoma cruzi (Dm28c strain). Biological evaluation display that 2-cyrhetrenyl-5-nitro-benzimidazole (Bzn-1) was more active than its ferrocene analogue (Bzn-2) and purely organic derivate (Bzn-3), associated with the electron-withdrawing properties of the (η5-C5H4)Re(CO)3 moiety. Finally, theoretical studies were carried out in order to elucidate the correlation between organometallic fragment, nitro-reduction potentials and trypanocidal activity.

In the research of new compounds with multifunctional applications, heterobinuclear palladium (II) complexes based on organometallic dithiocarbazates (DTCZs) have been isolated. The organometallic DTCZ ligands of the general formula [{(η5‐C5H4)‐CH=NNHC(S)SCH3}]MLn [MLn = Re (CO)3 (2a); Mn (CO)3 (2b); FeCp (2c)] were prepared by the reaction between formyl organometallic precursors (1a−c) with S‐methyldithiocarbazate. Subsequently, a two‐step reaction of 2a−c with: (i) K2[PdCl4] and (ii) PPh3 yielded heterobinuclear complexes [Pd{MLn(η5‐C5H4)‐CH=NNHC(S)SCH3}–(Cl)(PPh3)] [MLn = Re (CO)3 (3a); Mn (CO)3 (3b); FeCp (3c)]. All compounds were characterized by conventional spectroscopic techniques (infrared spectroscopy, nuclear magnetic resonance spectroscopy, mass spectrometry and elemental analysis). In addition, the molecular structures of 2a, 2c and 3c were determined by single‐crystal X‐ray diffraction. The new palladium (II) complexes (3a−c) were evaluated as antiproliferative agents against non‐small cell lung cancer cells (H1299 cells). Complexes 3a and 3b containing cyrhetrenyl‐ and cymantrenyl‐DTCZ ligands, respectively, were more active than their ferrocenyl analogue 3c. The activity was associated with the electron‐withdrawing properties of the (η5‐C5H4)M (CO)3 moieties and their better lipophilicity than that of the ferrocenyl analogue. In addition, we studied the capacity of metalloligands (2a−c) and palladium (II) complexes (3a−c) to remove methylene blue in water under UV–visible light irradiation. The results established that the complexes showed moderate efficiency and were less active than their corresponding free ligands.

The novel ferrocenyl sulfonyl hydrazide (2) and its homo (4) and heterobimetallic (5aand5b) imines were prepared and characterized. A comparative study of their electrochemical, spectroscopic and antitumor properties is also described.