Ruth Meléndrez-Luevano

Potential Amoebicidal Activity of Hydrazone Derivatives: Synthesis, Characterization, Electrochemical Behavior, Theoretical Study and Evaluation of the Biological Activity

Four new hydrazones were synthesized by the condensation of the selected hydrazine and the appropriate nitrobenzaldehyde. A complete characterization was done employing 1H- and 13C-NMR, electrochemical techniques and theoretical studies. After the characterization and electrochemical analysis of each compound, amoebicidal activity was tested in vitro against the HM1:IMSS strain of Entamoeba histolytica. The results showed the influence of the nitrobenzene group and the hydrazone linkage on the amoebicidal activity. meta-Nitro substituted compound 2 presents a promising amoebicidal activity with an IC50 = 0.84 μM, which represents a 7-fold increase in cell growth inhibition potency with respect to metronidazole (IC50 = 6.3 μM). Compounds 1, 3, and 4 show decreased amoebicidal activity, with IC50 values of 7, 75 and 23 µM, respectively, as a function of the nitro group position on the aromatic ring. The observed differences in the biological activity could be explained not only by the redox potential of the molecules, but also by their capacity to participate in the formation of intra- and intermolecular hydrogen bonds. Redox potentials as well as the amoebicidal activity can be described with parameters obtained from the DFT analysis.

(E)-1-(4-Nitro-benzyl-idene)-2,2-diphenyl-hydrazine.

The asymmetric unit of the title compound, C19H15N3O2, contains two molecules, both of which show an E conformation of the imine bond. The dihedral angles between the phenyl rings in the phenylhydrazine groups are 86.09 (6) and 83.41 (5)° in the two molecules. The 4-nitrobenzene rings show torsion angles of 4.4 (2) and 10.9 (2)° from the two C=N—N planes. In the crystal, C—H⋯π interactions and C—H⋯O hydrogen bonds are observed growing along the a, b and c axes, resulting in a complex supramolecular array.

Synthesis, characterization and evaluation of the substituent effect on the amoebicide activity of new hydrazone derivatives

A series of 10 hydrazones were synthesized by condensation of the selected hydrazine and the appropriate aldehyde. After the characterization and electrochemical analysis of each compound, amoebicidal activity was evaluated in vitro against the HM1:IMSS strain of Entamoeba histolytica. The results showed the influence of the nitrobenzene group and the hydrazone linkage over the amoebicidal activity. Compound 1 presents a promising amoebicidal activity with an IC50 = 0.98 μM, which represents a 7-fold increase in the potency of cell growth inhibition with respect to metronidazole (IC50= 6.8 μM). Moreover, compounds 2 and 4 present an amoebicidal activity comparable to the reference compound. These results show that the electronic environment of hydrazone derivatives reflected in redox potential values of the hydrazone linkage and the nitro group plays a fundamental role in the amoebicidal activity. The molecular structure of compound 1 was reported.

(E)-1-Benzyl-idene-2,2-diphenyl-hydrazine.

The asymmetric unit of the title compound, C19H16N2, contains two independent molecules, both of which show an E configuration with respect to the C=N bond. The dihedral angles between the phenyl rings bonded to the hydrazine group are 81.00 (10) and 88.34 (8)° in the two molecules. Intermolecular C—H⋯π interactions are observed in the crystal structure.

1-{(E)-[5-(2-Nitrophenyl)furan-2-yl]methylidene}-2,2-diphenylhydrazine

In the title compound, C23H17N3O3, the terminal benzene rings are oriented at dihedral angles of 3.67 (7), 76.02 (7) and 16.37 (7)° with respect to the central furan ring. In the crystal, molecules are connected via weak C—H⋯O hydrogen bonds, resulting in a three-dimensional supramolecular array.

(E)-1-(2,4-Di-nitro-benzyl-idene)-2,2-di-phenyl-hydrazine.

In the crystal of the title compound, C19H14N4O4, the asymmetric unit consists of two discrete molecules. The C=N bonds in both molecules show an E conformation. The dihedral angles between the C atoms of the 2,4-dinitrobenzene rings and the C=N—N planes are 13.52 (9) and 13.82 (9)° for the two molecules. In the crystal, C—H⋯O hydrogen bonds, mainly between the phenyl ring and the nitro group along the b axis.

N′-[5-(4-Nitro­phen­yl)furan-2-yl­methyl­idene]-N,N-diphenyl­hydrazine

The title compound, C23H17N3O3, has an E configuration with respect to the C=N bond. The dihedral angle between the two phenyl rings bonded to the hydrazine group is 86.45 (13)°. The furan ring makes dihedral angles of 3.4 (2) and 7.06 (13)°, respectively, with the methylidenehydrazine C=N—N plane and the benzene ring.

(1E,2E)-1,2-Bis(2,2-diphenyl­hydrazin-1-yl­idene)ethane

In the crystal structure of the title compound, C26H22N4, the molecule is located on an inversion centre and shows an E configuration with respect to each C=N bond. The dihedral angle between the phenyl rings in the diphenylhydrazone group is 83.69 (11)°. These two rings make dihedral angles of 30.53 (15) and 84.53 (16)° with the central N—N=C—C=N—N dihydrazonoethane plane. Intermolecular C—H⋯π interactions are observed.

Crystal structure of (E)-1-(2-nitro-benzyl-idene)-2,2-di-phenyl-hydrazine.

The title compound, C19H15N3O2, shows an E conformation of the imine bond. The dihedral angle between the planes of the phenyl rings in the diphenylhydrazine groups is 88.52 (4)°. The 2-nitrobenzene ring shows a torsion angle of 10.17 (8)° with the C=N—N plane. A short intramolecular C—H⋯O contact occurs. In the crystal, only van der Waals contacts occur between the molecules.

(E)-1,1-Diphenyl-2-(thio-phen-2-yl-methyl-idene)hydrazine.

The asymmetric unit of the title compound, C17H14N2S, consists of two crystallographically independent molecules with similar conformations. The dihedral angles between the phenyl rings are 89.32 (5) and 82.80 (5)° in the two molecules. In the crystal, molecules are linked by C—H⋯π interactions, forming a three-dimensional network.