Synthesis, crystal structure and Hirshfeld analysis of trans-bis-(2-{1-[(6R,S)-3,5,5,6,8,8-hexa-methyl-5,6,7,8-tetra-hydronaphthalen-2-yl]ethyl-idene}-N-methyl-hydrazinecarbo-thio-amidato-κ2N2,S)palladium(II) ethanol monosolvate.

The reaction between the (R,S)-fixolide 4-methyl-thio-semicarbazone and PdII chloride yielded the title compound, [Pd(C20H30N3S)2]·C2H6O {common name: trans-bis-[(R,S)-fixolide 4-methyl-thio-semicarbazonato-κ2 N 2 S]palladium(II) ethanol monosolvate}. The asymmetric unit of the title compound consists of one bis-thio-semicarbazonato PdII complex and one ethanol solvent mol-ecule. The thio-semicarbazononato ligands act as metal chelators with a trans configuration in a distorted square-planar geometry. A C-H⋯S intra-molecular inter-action, with graph-set motif S(6), is observed and the coordination sphere resembles a hydrogen-bonded macrocyclic environment. Additionally, one C-H⋯Pd anagostic inter-action can be suggested. Each ligand is disordered over the aliphatic ring, which adopts a half-chair conformation, and two methyl groups [s.o.f. = 0.624 (2):0.376 (2)]. The disorder includes the chiral carbon atoms and, remarkably, one ligand has the (R)-isomer with the highest s.o.f. value atoms, while the other one shows the opposite, the atoms with the highest s.o.f. value are associated with the (S)-isomer. The N-N-C(=S)-N fragments of the ligands are approximately planar, with the maximum deviations from the mean plane through the selected atoms being 0.0567 (1) and -0.0307 (8) Š(r.m.s.d. = 0.0403 and 0.0269 Å) and the dihedral angle with the respective aromatic rings amount to 46.68 (5) and 50.66 (4)°. In the crystal, the complexes are linked via pairs of N-H⋯S inter-actions, with graph-set motif R 2 2(8), into centrosymmetric dimers. The dimers are further connected by centrosymmetric pairs of ethanol mol-ecules, building mono-periodic hydrogen-bonded ribbons along [011]. The Hirshfeld surface analysis indicates that the major contributions for the crystal cohesion are [atoms with highest/lowest s.o.f.s considered separately]: H⋯H (81.6/82.0%), H⋯C/C⋯H (6.5/6.4%), H⋯N/N⋯H (5.2/5.0%) and H⋯S/S⋯H (5.0/4.9%).

Insight into Recent Drug Discoveries against Trypanosomatids and Plasmodium spp Parasites: New Metal-based Compounds.

Scaffolds of metal-based compounds can act as pharmacophore groups in several ligands to treat various diseases, including tropical infectious diseases (TID). In this review article, we investigate the contribution of these moieties to medicinal inorganic chemistry in the last seven years against TID, including American trypanosomiasis (Chagas disease), human African trypanosomiasis (HAT, sleeping sickness), leishmania, and malaria. The most potent metal-based complexes are displayed and highlighted in figures, tables and graphics; according to their pharmacological activities (IC50 > 10µM) against Trypanosomatids and Plasmodium spp parasites. We highlight the current progresses and viewpoints of these metal-based complexes, with a specific focus on drug discovery.

Crystal structure, Hirshfeld analysis and mol-ecular docking with the vascular endothelial growth factor receptor-2 of (3Z)-5-fluoro-3-(hy-droxy-imino)-indolin-2-one.

The reaction between 5-fluoro-isatin and hydroxyl-amine hydro-chloride in acidic ethanol yields the title compound, C8H5FN2O2, whose mol-ecular structure matches the asymmetric unit and is nearly planar with an r.m.s. deviation for the mean plane through all non-H atoms of 0.0363 Å. In the crystal, the mol-ecules are linked by N-H⋯N, N-H⋯O and O-H⋯O hydrogen-bonding inter-actions into a two-dimensional network along the (100) plane, forming rings with R22 (8) and R12 (5) graph-set motifs. The crystal packing also features weak π-π inter-actions along the [100] direction [centroid-to-centroid distance 3.9860 (5) Å]. Additionally, the Hirshfeld surface analysis indicates that the major contributions for the crystal structure are the O⋯H (28.50%) and H⋯F (16.40%) inter-actions. An in silico evaluation of the title compound with the vascular endothelial growth factor receptor-2 (VEGFR-2) was carried out. The title compound and the selected biological target VEGFR-2 show the N-H⋯O(GLU94), (CYS96)N-H⋯O(isatine) and (PHE95)N-H⋯O(isatine) inter-molecular inter-actions, which suggests a solid theoretical structure-activity relationship.

Hirshfeld analysis and mol-ecular docking with the RDR enzyme of 2-(5-chloro-2-oxoindolin-3-yl-idene)-N-methyl-hydrazinecarbo-thio-amide.

The acetic acid-catalyzed reaction between 5-chloro-isatin and 4-methyl-thio-semicarbazide yields the title compound, C10H9ClN4OS (I) (common name: 5-chloro-isatin-4-methyl-thio-semicarbazone). The mol-ecule is nearly planar (r.m.s. deviation = 0.047 Šfor all non-H atoms), with a maximum deviation of 0.089 (1) Šfor the O atom. An S(6) ring motif formed by an intra-molecular N-H⋯O hydrogen bond is observed. In the crystal, mol-ecules are linked by N-H⋯O hydrogen bonds, forming chains propagating along the a-axis direction. The chains are linked by N-H⋯S hydrogen bonds, forming a three-dimensional supra-molecular structure. The three-dimensional framework is reinforced by C-H⋯π inter-actions. The absolute structure of the mol-ecule in the crystal was determined by resonant scattering [Flack parameter = 0.006 (9)]. The crystal structure of the same compound, measured at 100 K, has been reported on previously [Qasem Ali et al. (2012 ▸). Acta Cryst. E68, o964-o965]. The Hirshfeld surface analysis indicates that the most important contributions for the crystal packing are the H⋯H (23.1%), H⋯C (18.4%), H⋯Cl (13.7%), H⋯S (12.0%) and H⋯O (11.3%) inter-actions. A mol-ecular docking evaluation of the title compound with the ribonucleoside diphosphate reductase (RDR) enzyme was carried out. The title compound (I) and the active site of the selected enzyme show Cl⋯H-C(LYS140), Cg(aromatic ring)⋯H-C(SER71), H⋯O-C(GLU200) and FeIII⋯O⋯FeIII inter-molecular inter-actions, which suggests a solid theoretical structure-activity relationship.

Crystal structure of (2E)-3-[4-(di-methyl-amino)-phen-yl]-1-(thio-phen-2-yl)prop-2-en-1-one.

The equimolar reaction between 4-(di-methyl-amino)-benzaldehyde and 2-acetyl-thio-phene in basic ethano-lic solution yields the title compound, C15H15NOS, whose mol-ecular structure matches the asymmetric unit. The mol-ecule is not planar, the dihedral angle between the aromatic and the thio-phene rings being 11.4 (2)°. In the crystal, mol-ecules are linked by C-H⋯O and weak C-H⋯S inter-actions along [100], forming R22 (8) rings, and by weak C-H⋯O inter-actions along [010], forming chains with a C(6) graph-set motif. In addition, mol-ecules are connected into centrosymmetric dimers by weak C-H⋯π inter-actions, as indicated by the Hirshfeld surface analysis. The most important contributions for the crystal structure are the H⋯H (46.50%) and H⋯C (23.40%) inter-actions. The crystal packing resembles a herringbone arrangement when viewed along [100]. A mol-ecular docking calculation of the title compound with the neuraminidase enzyme was carried out. The enzyme shows (ASN263)N-H⋯O, (PRO245)C-H⋯Cg(thio-phene ring) and (AGR287)C-H⋯N inter-molecular inter-actions with the title compound. The crystal structure was refined as a two-component twin with a fractional contribution to the minor domain of 0.0181 (8).

Crystal structure of (3E)-5-nitro-3-(2-phenyl-hydrazinyl-idene)-1H-indol-2(3H)-one.

The reaction between 5-nitro-isatin and phenyl-hydrazine in acidic ethanol yields the title compound, C14H10N4O3, whose mol-ecular structure deviates slightly from a planar geometry (r.m.s. deviation = 0.065 Šfor the mean plane through all non-H atoms). An intra-molecular N-H⋯O hydrogen bond is present, forming a ring of graph-set motif S(6). In the crystal, mol-ecules are linked by N-H⋯O and C-H⋯O hydrogen-bonding inter-actions into a two-dimensional network along (120), and rings of graph-set motif R22(8), R22(26) and R44(32) are observed. Additionally, a Hirshfeld surface analysis suggests that the mol-ecules are stacked along [100] through C=O⋯Cg inter-actions and indicates that the most important contributions for the crystal structure are O⋯H (28.5%) and H⋯H (26.7%) inter-actions. An in silico evaluation of the title compound with the DHFR enzyme (di-hydro-folate reductase) was performed. The isatin-hydrazone derivative and the active site of the selected enzyme show N-H⋯O(ASP29), N-H⋯O(ILE96) and Cg⋯Cg(PHE33) inter-actions.

Crystal structure of N-ethyl-2-(1,2,3,4-tetra-hydro-naphthalen-1-yl-idene)hydrazinecarbo-thio-amide.

There are two crystallographically independent mol-ecules in the asymmetric unit of the title compound, C13H17N3S, one of them being disordered over the methyl group [site-occupancy ratio = 0.705 (5):0.295 (5)]. The maximum r.m.s. deviations from the mean plane of the non-H atoms for the tetra-lone fragments amount to 0.4572 (17) and 0.4558 (15) Å. The N-N-C-N fragments are not planar and torsion angles are -9.4 (2) and 8.3 (2)°. In the crystal, the mol-ecules are linked by weak N-H⋯S inter-actions into chains along [100] with graph-set motif C(4) and connected by weak N-H⋯S and C-H⋯S inter-actions, forming R21(10) rings. The Hirshfeld surface analysis indicates that the most important contributions for the crystal packing are the H⋯H (64.20%), H⋯S (12.60%) and H⋯C (12.00%) inter-actions. The crystal packing resembles a herringbone arrangement when viewed along [001].

Crystal structure of (E)-2-[1-(benzo[d][1,3]dioxol-5-yl)ethyl-idene]-N-methyl-hydrazine-1-carbo-thio-amide.

In the title compound, C11H13N3O2S, there is a short intra-molecular N-H⋯N contact. The benzo[d][1,3]dioxole ring system is approximately planar (r.m.s. deviation = 0.025 Å) and makes a dihedral angle of 56.83 (6)° with the mean plane of the methyl-thio-semicarbazone fragment [-N-N-C(=S)-N-C; maximum deviation = 0.1111 (14) Šfor the imino N atom]. In the crystal, mol-ecules are linked via pairs of N-H⋯S hydrogen bonds, forming inversion dimers. The dimers are connected by N-H⋯S hydrogen bonds into layers parallel to (100). The H atoms of both methyl groups are disordered over two sets of sites and were refined with occupancy ratios of 0.5:0.5 and 0.75:0.25.

Crystal structure of (E)-2-[(2S,5R)-2-isopropyl-5-methyl-cyclo-hexyl-idene]hydrazine-1-carbo-thio-amide.

The title compound, C11H21N3S, consists of a menthone moiety attached to an extended thio-semicarbazone group with the N-N-C-N torsion angle being 11.92 (16)°. The cyclo-hexane ring has a chair conformation and the conformation about the C=N bond is E. In the crystal, mol-ecules are linked via pairs of N-H⋯S hydrogen bonds, forming chains along the a axis. The absolute structure could be assigned with reference to the starting material, i.e. enanti-opure (-)-menthone [Flack parameter = 0.05 (5)].

1-(2H-1,3-Benzodioxol-5-yl)ethanone thio-semicarbazone.

In the title compound, C10H11N3O2S, the 1,3-benzodioxole and hydrazinecarbothio-amide fragments are nearly planar [(mean deviations from planarity for non-H atoms of 0.0325 (12) Šand 0.0707 (10) Å, respectively] and subtend a dihedral angle of 29.06 (5)°. In the crystal, mol-ecules are linked by pairs of almost linear N-H⋯S hydrogen bonds, forming inversion dimers. These dimers are additionally connected by weaker and strongly bent N-H⋯S inter-actions into chains along [101]. There is one additional weak N-H⋯O contact which, if considered as an inter-action, leads to the formation of a three-dimensional network.