Synthesis, characterization and antiparasitic activity of organometallic derivatives of the anthelmintic drug albendazole.

Helminthiases, a group of neglected tropical diseases, affect more than one billion people mainly in tropical and subtropical regions. Moreover, major intestinal protozoa have a significant impact on global public health. Albendazole (ABZ) is a broad-spectrum anthelmintic recommended by the World Health Organisation (WHO). However, drug resistance is emerging due to its widespread use. In order to tackle this problem, taking into account the spectacular results obtained with ferroquine, an organometallic derivatization of the antimalarial drug chloroquine, we have prepared, in this study, a series of new ferrocenyl and ruthenocenyl derivatives of the organic drug ABZ and assessed their activity against different helminths and protozoans, namely Trichuris muris, Heligmosomoides polygygrus, Schistosoma mansoni, Giardia lamblia, Haemonchus contortus and Toxoplasma gondii. The ferrocene-containing ABZ analogue 2d exhibited over 70% activity against T. muris adults in vitro at 200 µM and no toxicity to mammalian cells (IC50 >100 µM). H. polygyrus adults were not affected by any of the derivatives tested. Against T. gondii, the ferrocene-containing ABZ analogues 1a and 2d showed better in vitro activity than ABZ and low toxicity to the host cells. The activity of the analogous ruthenocenyl compound 2b against S. mansoni and T. gondii in vitro might be attributed to its toxicity towards the host cells rather than a specific antiparasitic activity. These results demonstrate that the derivatives show a species specific in vitro activity and the choice of the organometallic moieties attached to the organic drug is playing a very important role. Two of our organometallic compounds, namely 1b and 2d, were tested in T. muris infected mice. At a 400 mg kg-1 dose, the compounds showed moderate worm burden reductions but low worm expulsion rates. Overall, this work, which is one of the first studies reporting the potential of organometallic compounds on a very broad range of parasitic helminths and protozoan, is a clear confirmation of the potential of organometallic complexes against parasites of medical and veterinary importance.

(E,E)-3-Methyl-2,5-bis-(4-methyl-benzyl-idene)cyclo-penta-none: synthesis, characterization, Hirshfeld surface analysis and anti-bacterial activity.

The title compound, (E,E)-3-methyl-2,5-bis-(4-methyl-benzyl-idene)cyclo-penta-none (MBMCP), C22H22O, was obtained by Claisen-Schmidt condensation of 4-methyl-benzaldehyde with 3-methyl-cyclo-penta-none in good yield. The structure of MBMCP was studied using UV, FT-IR and Raman spectroscopy, single-crystal X-ray diffraction (XRD) measurements, and 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. The mol-ecular structure of MBMCP is fully extended in the E,E configuration. C-H⋯π stacking inter-actions play a significant role in the stabilization of the mol-ecular packing. Hirshfeld surface analysis was used to qu-antify the non-covalent inter-actions in the crystal lattice. Microbiological studies were performed to investigate the anti-microbial activity of this new product.

Syntheses, supramolecular networks and Hirshfeld surface and thermal analyses of two new cadmium chloride coordination polymers with an N,O-chelating ligand.

Two new coordination polymers, namely poly[[(3-aminopyrazin-4-ium-2-carboxylate-κ2N1,O)di-µ-chlorido-cadmium(II)] monohydrate], {[CdCl2(C5H5N3O2)]·H2O}n, (1), and poly[2-amino-3-carboxypyrazin-1-ium [(3-aminopyrazine-2-carboxylato-κ2N1,O)di-µ-chlorido-cadmium(II)] monohydrate], {(C5H6N3O2)[Cd(C5H4N3O2)Cl2]·H2O}n, (2), have been synthesized from the reaction of cadmium(II) chloride and 3-aminopyrazine-2-carboxylic acid (Hapca) under mild conditions in acidic media. The two coordination polymers have been characterized by single-crystal X-ray diffraction and show chloride-bridged zigzag chains with octahedrally coordinated metal ions, where Hapca acts as a bidentate ligand via the π-conjugated N atom and a carboxylate O atom. The chains are further interconnected via noncovalent interactions into three-dimensional supramolecular networks. The dominant H...O and H...Cl interactions for both compounds were quantified using Hirshfeld surface analysis. The thermal stability and topological analysis of the two-dimensional networks of (1) and (2) are also discussed.

Two hydrazones derived from 1-aryl-3-(p-substituted phenyl)prop-2-en-1-one: synthesis, crystal structure, Hirshfeld surface analysis and in vitro biological properties.

Two chalcones were synthesized by the aldolic condensation of enolizable aromatic ketones with substituted benzaldehydes under Claisen-Schmidt reaction conditions and then treated with 2,4-dinitrophenylhydrazine to yield their corresponding hydrazones. The two (E,Z)-2,4-dinitrophenylhydrazone structures, namely (Z)-1-(2,4-dinitrophenyl)-2-[(E)-3-(4-methylphenyl)-1-phenylallylidene]hydrazine, C22H18N4O4, (H1), and (Z)-1-[(E)-3-(4-chlorophenyl)-1-(naphthalen-1-yl)allylidene]-2-(2,4-dinitrophenyl)hydrazine, C25H17ClN4O4, (H2), were isolated by recrystallization and characterized by FT-IR, UV-Vis, single-crystal and powder X-ray diffraction methods. The UV-Vis spectra of the hydrazones have been studied in two organic solvents of different polarity. It was found that (H2) has a molar extinction coefficient larger than 40000. Single-crystal X-ray diffraction analysis reveals that the molecular zigzag chains of (H1) and (H2) are interconnected through noncovalent contacts. A quantitative analysis of the intermolecular interactions in the crystal structures has been performed using Hirshfeld surface analysis. All the synthesized chalcones and hydrazones were evaluated for their antibacterial and antioxidant activities. Results indicate that the studied compounds show significant activity against Gram negative Escherichia coli strain and the chalcone 3-(4-methylphenyl)-1-phenylprop-2-en-1-one, (C1), was the most effective. In addition, only hydrazone (H1) displayed a moderate DPPH (2,2-diphenyl-1-picryl hydrazyl) scavenging efficiency.

Synthesis, X-ray diffraction and Hirshfeld surface analysis of two new hybrid dihydrate compounds: (C6H22N4)[SnCl6]Cl2·2H2O and (C8H24N4)[SnCl6]Cl2·2H2O.

Two new organic-inorganic hybrid compounds, tri-ethyl-ene-tetra-ammonium hexa-chlorido-stannate (IV) dichloride dihydrate, (C6H22N4)[SnCl6]Cl2·2H2O, (I), and 1,4-bis-(2-ammonio-eth-yl)piperazin-1,4-diium hexa-chlorido-stannate (IV) dichloride dihydrate, (C8H24N4)[SnCl6]Cl2·2H2O, (II), have been synthesized from the same starting materials. In each case both the cations and anions are located about inversion centers. Their crystal structures exhibits alternating inorganic and organic stacking sheets in (I) and layers in (II), with Cl- ions and water mol-ecules occupying the space in between. The cohesion of the three-dimensional frameworks are governed by N-H⋯Cl, N-H⋯O, C-H⋯Cl and O-H⋯Cl hydrogen bonds. Hirshfeld surface analysis of both crystal structures indicates that the H⋯Cl/Cl⋯H contacts exert an important influence on the stabilization of the packing.

Selective synthesis of (3-ferrocenylprop-2-en-1-yl)triphenylphosphonium iodide: crystal structure determination of two polymorphs.

This work is part of a project studying the reactivity of a new ferrocenyl allylammonium salt, [3-(trimethylazaniumyl)prop-1-en-1-yl]ferrocene iodide, (1+)·I-, with different nucleophiles. With nitrogen-based nucleophiles, different ferrocenyl allylamine isomers have been synthesized successfully in good yield. Optimization of the basicity of the reaction medium has allowed selection of the best operating conditions to obtain the targeted isomer. In a similar way and in order to introduce phosphorus-containing functional groups, the reaction of ammonium salt (1+)·I- with a phosphorus nucleophile, namely triphenylphosphane, was attempted. It was then possible to isolate single crystals of (3-ferrocenylprop-2-en-1-yl)triphenylphosphonium iodide, [Fe(C5H5)(C26H23P)]I, which is shown to crystallize in two concomitant polymorphic forms, viz. a triclinic form, (I), in the space group P-1, and a monoclinic form, (II), in the space group P21/c. In the inter-ion packing of polymorph (I), the cations form bilayer ribbons via C-H...π and π-π stacking interactions. In polymorph (II), where π-π interactions do not occur, adjacent molecules are joined by C-H...π interactions into a one-dimensional helical arrangement along the b axis.

A simple hydrated salt with a complex hydrogen-bonding network: tetrakis(5-amino-3-carboxy-4H-1,2,4-triazol-1-ium) hexachloridocadmate(II) tetrahydrate.

In the title cadmium chloride salt, (C3H5N4O2)4[CdCl6]·4H2O, the asymmetric unit comprises two N-protonated 5-amino-3-carboxy-4H-1,2,4-triazol-1-ium cations, half a [CdCl6](4-) anion and two molecules of water. The Cd(2+) cation is located on a centre of inversion and is coordinated by six chloride anions, forming a distorted octahedron. In the crystal structure, alternating layers of cations and anions are arranged along the [101] direction, forming a three-dimensional supramolecular network via a combination of hydrogen-bonding and aromatic stacking interactions.

Bis(3-amino-pyrazine-2-carboxyl-ato-κ(2) N (1),O)di-aqua-nickel(II) dihydrate.

In the title compound, [Ni(C5H4N3O2)2(H2O)2]·2H2O, the Ni(II) ion lies on an inversion center and is coordinated in an slightly distorted octa-hedral environment by two N,O-chelating 3-amino-pyrazine-2-carboxyl-ate (APZC) ligands in the equatorial plane and two trans-axial aqua ligands. In the crystal, O-H⋯O, N-H⋯O and O-H⋯N hydrogen bonds involving the solvent water mol-ecules, aqua and APZC ligands form layers parallel to (010). These layers are linked further via O-H⋯O, N-H⋯O and C-H⋯O hydrogen bonds involving the axial aqua ligands, amino groups and the carboxyl-ate groups of the APZC ligands, forming a three-dimensional network.

4-(Dimethyl-amino)-pyridinium tetra-chloridoferrate(III).

The title salt, (C7H11N2)[FeCl4], consists of one essentially planar (the r.m.s. deviation for all non-H atoms being 0.004 Å) 4-(dimethyl-amino)-pyridinium cation and a tetra-hedral tetra-chloridoferrate(III) anion. The cations and anions are arranged in layers parallel to (010). Besides electrostatic inter-actions, the crystal packing features N-H⋯Cl and C-H⋯Cl hydrogen bonds between cations and anions, forming a three-dimensional network.

Bis(3-amino-pyrazine-2-carboxyl-ato-κ(2)N(1),O)diaqua-cobalt(II).

In the title compound, [Co(C(5)H(4)N(3)O(2))(2)(H(2)O)(2)], the Co(II) atom is situated on a twofold rotation axis and is N,O-chelated by two 3-amino-pyrazine-2-carboxyl-ate anions and additionally bonded to the O atoms of two water mol-ecules, leading to a slightly distorted octa-hedral coordination environment. The crystal packing is dominated by inter-molecular O-H⋯O, O-H⋯N and N-H⋯O hydrogen bonding involving the water mol-ecules and amino groups as donors and carboxyl-ate O atoms, as well as the non-coordinating heterocyclic N atoms as acceptors, resulting in a three-dimensional network. An intra-molecular N-H⋯O hydrogen bond is also observed.

Bis[4-(di-methyl-amino)-pyridinium] tetra-chlorido-cuprate(II).

The asymmetric unit of the title salt, (C7H11N2)2[CuCl4], comprises half a tetrahedral tetra-chlorido-cuprate anion, being located on a twofold axis, and a protonated 4-(di-methyl-amino)-pyridine cation. The geometry around the Cu(II) ion is highly distorted with the range of Cl-Cu-Cl angles being 94.94 (1)-141.03 (1)°. The crystal structure is stabilized by N-H⋯Cl and C-H⋯Cl hydrogen bonds. In the three-dimensional network, cations and anions pack in the lattice so as to generate chains of [CuCl4](2-) anions separated by two orientations of cation layers, which are inter-locked through π-π stacking contacts between pairs of pyridine rings, with centroid-centroid distances of 3.7874 (7) Å.

5-Amino-3-carb-oxy-1H-1,2,4-triazol-4-ium nitrate monohydrate.

The two-dimensional crystal packing of the title compound, C(3)H(5)N(4)O(2) (+)·NO(2) (-)·H(2)O, results from the stacking of well separated layers (i.e. with nothing between the layers) parallel to the (-113) plane in which adjacent cations adopt a head-to-head arrangement such that two -COOH groups are linked via two water mol-ecules (the water O atom behaves simultaneously as donor and acceptor of hydrogen bonds) and two -NH(2) groups are linked through two nitrate anions. This arrangement leads to alternating hydro-philic and hydro-phobic zones in which O-H⋯O and N-H⋯O hydrogen bonds, respectively, are observed.

Bis(5-amino-3-carb-oxy-1H-1,2,4-triazol-4-ium) dihydrogenphosphate nitrate 5-amino-1H-1,2,4-triazol-4-ium-3-carboxyl-ate.

In the title compound, 2C(3)H(5)N(4)O(2) (+)·H(2)PO(4) (-)·NO(3) (-)·C(3)H(4)N(4)O(2), three independent 5-amino-1H-1,2,4-triazol-3-carb-oxy-lic acid moieties are observed. Two are in the form of cations, while the third is in the zwitterionic form. The triazole rings in the two cations are almost coplanar, making an angle of 4.11 (7)°. Layers parallel to the (20-1) plane, resulting from hydrogen bonding of the organic mol-ecules and the nitrate anions, are linked via H(2)PO(4) (-) infinite zigzag chains running parallel to the c axis. The crystal studied was an inversion twin, with refined components of 0.33 (7) and 0.67 (7).

2-Amino-3-carb-oxy-pyridinium chloride hemihydrate.

The asymmetric unit of the title compound, C(6)H(7)N(2)O(2) (+)·Cl(-)·0.5H(2)O, consists of two protonated 2-amino-3-carb-oxy-pyridine cations, two chloride anions and one mol-ecule of water. The crystal packing can be described as alternating layers of cations and anions parallel to (110), which are linked together by O(w)-H⋯Cl inter-actions. In the crystal, four types of classical hydrogen bonds are observed, viz. cation-anion (O-H⋯Cl and N-H⋯Cl), cation-cation (N-H⋯O), cation-water (N-H⋯O(w)) and water-anion (O(w)-H⋯Cl), resulting in the formation of an infinite three-dimensional network.