A second crystalline modification of 2-{3-methyl-2-[(2Z)-pent-2-en-1-yl]cyclo-pent-2-en-1-yl-idene}hydrazinecarbo-thio-amide.

A second crystalline modification of the title compound, C12H19N3S [common name: cis-jasmone thio-semicarbazone] was crystallized from tetra-hydro-furane at room temperature. There is one crystallographic independent mol-ecule in the asymmetric unit, showing disorder in the cis-jasmone chain [site-occupancy ratio = 0.590 (14):0.410 (14)]. The thio-semicarbazone entity is approximately planar, with the maximum deviation from the mean plane through the N/N/C/S/N atoms being 0.0463 (14) Š[r.m.s.d. = 0.0324 Å], while for the five-membered ring of the jasmone fragment, the maximum deviation from the mean plane through the carbon atoms amounts to 0.0465 (15) Š[r.m.s.d. = 0.0338 Å]. The mol-ecule is not planar due to the dihedral angle between these two fragments, which is 8.93 (1)°, and due to the sp 3-hybridized carbon atoms in the jasmone fragment chain. In the crystal, the mol-ecules are connected by N-H⋯S and C-H⋯S inter-actions, with graph-set motifs R 2 2(8) and R 2 1(7), building mono-periodic hydrogen-bonded ribbons along [010]. A Hirshfeld surface analysis indicates that the major contributions for the crystal cohesion are H⋯H (67.8%), H⋯S/S⋯H (15.0%), H⋯C/C⋯H (8.5%) and H⋯N/N⋯H (5.6%) [only non-disordered atoms and those with the highest s.o.f. were considered]. This work reports the second crystalline modification of the cis-jasmone thio-semicarbazone structure, the first one being published recently [Orsoni et al. (2020 ▸). Int. J. Mol. Sci. 21, 8681-8697] with the crystals obtained in ethanol at 273 K.

Potential role of a newly AChE reactivator in the depressive-like behavior induced by malathion.

AChE inhibition caused by exposure to organophosphate (OP) compounds is strongly related to behavioural disorders such as depression. Malathion is an OP that already has a relationship between its exposure and behavioural changes, although few data still have its effects in a longer exposure protocol. In addition, intoxication therapy is based on the use of atropine-oxime which still has its controversial efficacy depending on the type of compound. For this, (3Z)-5-Chloro-3-(hydroxyimino)indolin-2-one (Cℓ-HIN), a compound that has properties of isatin and oxime in its structure, have shown reactivating properties in the activity of AChE that have been added to antidepressant-like effects in rats exposed to malathion in acute protocol. In this sense, effects of Cℓ-HIN on the depressive-like behaviour and AChE activity were evaluated in a protocol of subchronic exposure to malathion in rats. Male wistar rats were co-treated with Cℓ-HIN [5 mg/kg, p.o.] and/or malathion [1 or 10 mg/kg, i.p] for 20 days. The exposure to both doses of malathion increased immobility time of rats on the forced swimming test (FST). Besides, malathion inhibited the AChE activity in the prefrontal cortex of rats, but any significant difference was observed in the hippocampus. Cℓ-HIN protected against increased immobility time in the FST of those rats exposed to a dose of 1 mg/kg of malathion. Similarly, Cℓ-HIN was able to reactivate AChE activity only in that group exposed to the lowest dose of malathion. Collectively, the results of this study suggest that Cℓ-HIN is an oxime capable of reactivating AChE inhibited and presents na antidepressant-like effect in cases of prolonged exposure to malathion.

Antidepressant-like effect of (3Z)-5-Chloro-3-(hydroxyimino)indolin-2-one in rats exposed to malathion: Involvement of BDNF-Trkß pathway and AChE.

BACKGROUND: Organophosphorus pesticides exert their toxic effects mainly by the inhibition of acetylcholinesterase (AChE), which is related to emotional disorders, such as depression. Atropine-oximes therapy is commonly used; however, the efficacy of oximes in the reactivation of AChE has been inconsistent. The objective of this study was to investigate the possible neuroprotective effect of (3Z)-5-Chloro-3-(hydroxyimino)indolin-2-one (Cℓ-HIN), a compound that combines the isatin and oxime functional groups, in rats exposed to malathion. The effect of Cℓ-HIN on the AChE activity and the BDNF-Trkß pathway in the prefrontal cortex of malathion-exposed rats were tested. METHODS: Wistar male rats were co-treated with Cℓ-HIN [50 mg/kg (p.o.) (3 mL/kg)] and/or malathion [250 mg/kg (i.p.) (5 mL/kg)] and performed behavioral tests twelve hours after these exposures. RESULTS: The Cℓ-HIN reversed the increased immobility time in the forced swimming test and the decreased grooming time in the splash test induced by malathion, but any significant difference was observed in locomotion analysis. These results demonstrate the antidepressant-like effect of Cℓ-HIN. The cortical AChE activity was reactivated by Cℓ-HIN in rats exposed to malathion. Malathion induced an increase in Trkß and a decrease in BDNF levels in the prefrontal cortex of rats, which were avoided by Cℓ-HIN. CONCLUSION: These findings support the hypothesis that Cℓ-HIN is an AChE reactivator with antidepressant-like properties, which is related to the improvement of BDNF-Trkß signaling after acute exposure to malathion in rats. Thus, the results allow suggesting the potential use of Cℓ-HIN as an oxime-based therapy against the neurotoxic effects of malathion.

Synthesis, crystal structure and Hirshfeld analysis of a crystalline compound comprising a 1/1 mixture of 1-[(1R,4S)- and 1-[(1S,4R)-1,7,7-trimethyl-2-oxobi-cyclo[2.2.1]heptan-3-yl-idene]hydrazinecarbo-thio-amide.

The equimolar reaction between a racemic mixture of (R)- and (S)-camphorquinone with thio-semicarbazide yielded the title compound, C11H17N3OS [common name: (R)- and (S)-camphor thio-semicarbazone], which maintains the chirality of the methyl-ated chiral carbon atoms and crystallizes in the centrosymmetric space group C2/c. There are two mol-ecules in general positions in the asymmetric unit, one of them being the (1R)-camphor thio-semicarbazone isomer and the second the (1S)- isomer. In the crystal, the mol-ecular units are linked by C-H⋯S, N-H⋯O and N-H⋯S inter-actions, building a tape-like structure parallel to the (01) plane, generating R 2 1(7) and R 2 2(8) graph-set motifs for the H⋯S inter-actions. The Hirshfeld surface analysis indicates that the major contributions for crystal cohesion are from H⋯H (55.00%), H⋯S (22.00%), H⋯N (8.90%) and H⋯O (8.40%) inter-actions.

Pre-clinical evidence of safety and protective effect of isatin and oxime derivatives against malathion-induced toxicity.

The inhibition of acetylcholinesterase (AChE) is a common outcome caused by organophosphorus (OPs) intoxication. Although inconsistent, the standard treatment consists of a muscarinic receptor antagonist (atropine) and AChE-reactivating molecules such as oximes. This study proposes to test unpublished compounds which contain the moieties of isatin and/or oxime have protective effects against the toxicity induced by malathion in two animal models: Artemia salina and Rattus norvegicus (Wistar rats). The lethality was assessed in A salina, and the calculated LD50 to (3Z)-5-chloro-3-(hydroxyimino) indolin-2-one oxime (Cℓ-HIN) and 2-(5-chloro-2-oxoindolin-3-ylidene)-hydrazinecarbothioamide (Cℓ-OXHS) was higher than 1000 µM while to 3-(phenylhydrazono) butan-2-one oxime (PHBO) was 38 µM. Our screening showed that Cℓ-HIN seems to be the most promising molecule, with low toxicity to A salina, protection against mortality (with or without atropine) and AChE inhibition induced by malathion. Similarly, the oral administration of 300 mg/kg of Cℓ-HIN induced low or no toxicity in rats. The plasma butyrylcholinesterase (BChE) and cortical AChE activities were reactivated by Cℓ-HIN (50 mg/kg, p.o.) in rats exposed to malathion (250 mg/kg, i.p). No difference was observed in paraoxonase-1 (PON-1) activity among groups treated. In conclusion, Cℓ-HIN restored the cholinesterase activities inhibited by malathion in A salina and rats with low toxicity in both. Thus, the data provide evidence that Cℓ-HIN, a compound that combines isatin and oxime functional groups, is safe and has important properties to reactivate the cholinesterases inhibited by malathion. In addition, we demonstrate the importance of a preliminary assessment in an alternative model in order to reduce the use of mammalians in drug discovery.

(3Z)-5-Chloro-3-(Hydroxyimino)indolin-2-one attenuates hyperglycemia, increased hepatic glycogen content and hepatic damage induced by malathion acute exposure in rats.

BACKGROUND: Organophosphorus pesticides (OP's) are heavily constituted in agriculture, gardens, home and veterinary and although it is useful, there are concerns about the environment, safety and health of human and animals. In this study, we investigated the effects of a new oxime, (3Z)-5-Chloro-3-(Hydroxyimino)indolin-2-one (OXIME) against the alterations induced by malathion, an OP insecticide, acute exposure on markers of hepatic damage, glucose homeostasis, oxidative stress in rats cholinesterase (ChE) activity in rats. METHODS: Adult male Wistar rats were divided into four groups: Control; Malathion; OXIME; and Malathion+OXIME. Twelve hours after co-treatment with malathion (250 mg/kg, i.p.) and/or OXIME (50 mg/kg, i.g.), the plasma and liver samples were collected for biochemical analyses. RESULTS: The OXIME blocked the increase of plasma markers of hepatic function (AST and ALP) and the enzymatic inhibition of catalase and glutathione reductase in the liver of malathion-treated rats. Moreover, the hepatic cholinesterases inhibition induced by malathion acute exposure was suppressed by OXIME treatment. As assessed, a single dose of OXIME lowered the glycemia levels and hepatic glycogen content enhanced by malathion. CONCLUSIONS: This study suggests promise effects of (3Z)-5-Chloro-3-(Hydroxyimino) indolin-2-one against the hyperglycemia and the hepatic damage induced by malathion acute exposure, as well as its use as a ChE activity reactivator.

Crystal structure and Hirshfeld analysis of trans-bis-(5-fluoro-indoline-2,3-dione 3-oximato-κ2O2,N3)-trans-bis-(pyridine-κN)copper(II).

The reaction in methanol of CuII acetate monohydrate with 5-fluoro-isatin 3-oxime deprotonated with KOH in a 1:2 molar ratio and recrystallization from pyridine yielded the title compound, [Cu(C8H4FN2O2)2(C5H5N)2]. In the centrosymmetric complex, the anionic form of the isatin oxime acts as a κ2N,O donor, building five-membered metallarings. The CuII cation is sixfold coordinated in a slightly distorted octa-hedral environment by two trans, equatorial, anionic isatin derivatives and two trans pyridine ligands in axial positions. The complexes are linked by hydrogen bonding into a three-dimensional network, which is also stabilized by π-π stacking inter-actions [centroid-to-centroid distance = 3.7352 (9) Å] and C-H⋯π contacts. The Hirshfeld surface analysis indicates that the major contributions for the crystal packing are H⋯H (31.80%), H⋯C (24.30%), H⋯O (15.20%) and H⋯F (10.80%). This work is the second report in the literature of a crystal structure of a coordination compound with isatin 3-oxime ligands (coordination chemistry).

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 (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 (Z)-2-(5-fluoro-2-oxoindolin-3-yl-idene)hydrazinecarbo-thio-amide.

In the title compound, C9H7FN4OS, the mol-ecules are almost planar, with an r.m.s. deviation of 0.047 (3) Šfrom the mean plane defined by the non-H atoms and a maximum deviation of 0.123 (2) Šfor the amine N atom. The torsion angle for the N-N-C-S unit is 176.57 (19)°. In the crystal, mol-ecules are linked into inversion dimers via pairs of N-H⋯F hydrogen bonds and, additionally, through N-H⋯O and N-H⋯S hydrogen bonds, building a two-dimensional hydrogen-bond network parallel to the (103) plane. An intra-molecular N-H⋯O inter-action is also observed.

Crystal structure of bis-{µ-4-methyl-N'-[3-(oxido-imino)-butan-2-yl-idene]benzene-sulfono-hydrazidato}bis-[(dimethyl sulfoxide-κO)copper(II)].

In the title compound, [Cu2(C11H13N3O3S)2(C2H6OS)2], the Cu(II) cation is N,N',O-chelated by a deprotonated hy-droxy-imino-tosyl-hydrazone ligand and coordinated by a dimethyl sulfoxide mol-ecule. One O atom from the adjacent hy-droxy-imino-tosyl-hydrazone ligand bridges the Cu(II) cation, forming the centrosymmetric dimeric complex. The cation is in an overall distorted N2O3 square-pyramidal coordination environment. The methyl-benzene ring is twisted with respect to the hydrazine fragment, with a dihedral angle of 89.54 (9)° between the planes. An intra-molecular C-H⋯O hydrogen bond occurs. In the crystal, mol-ecules are linked by weak C-H⋯O and C-H⋯S inter-actions. Weak π-π stacking is also observed between parallel benzene rings of adjacent mol-ecules, the centroid-centroid distance being 3.9592 (17) Å.

2-(5-Iodo-2-oxoindolin-3-yl-idene)hydrazinecarbo-thio-amide including an unknown solvate.

The mol-ecule of the title compound, C9H7IN4OS, is almost planar (r.m.s. deviation = 0.0373 Å). In the mol-ecule, N-H⋯N and N-H⋯O hydrogen bonds generate, respectively, S(5) and S(6) ring motifs. In the crystal, mol-ecules are linked via N-H⋯O hydrogen bonds, forming chains propagating along [010]. These chains are linked via S⋯I contacts [3.4915 (16) Å], forming sheets lying parallel to (100). A region of disordered electron density, probably a disordered tetra-hydro-furan solvent mol-ecule, was treated using the SQUEEZE routine in PLATON [Spek (2009). Acta Cryst. D65, 148-155]. The formula mass and unit-cell characteristics were not taken into account during refinement.

2-(5-Chloro-2-oxoindolin-3-yl-idene)hydrazinecarbo-thio-amide.

The title mol-ecule, C9H7ClN4OS, is almost planar, with an r.m.s. deviation of 0.034 (2) Šfor the mean plane through all the non-H atoms. Intra-molecular N-H⋯O and N-H⋯N hydrogen bonds form S(6) and S(5) ring motifs, respectively. In the crystal, mol-ecules are assembled into inversion dimers through pairs of co-operative N-H⋯Cl inter-actions. These dimers are connected along the b axis by N-H⋯O and N-H⋯S hydrogen bonds, generating layers parallel to (103). The layers are further connected along the a axis into a three-dimensional network, through weak π-π stacking inter-actions [centroid-centroid distance = 3.849 (2) Å].

Bis{4-phenyl-1-[1-(pyridin-2-yl-κN)ethyl-idene]thio-semicarbazidato-κ(2)N(1),S}cadmium.

The reaction of cadmium acetate dihydrate with 2-acetyl-pyridine (4-phenyl-thio-semicarbazone) yielded the title compound, [Cd(C(14)H(13)N(4)S)(2)]. The Cd(II) atom is six-coordin-ated in a distorted octa-hedral environment by two deproton-ated thio-semicarbazone ligands acting in a tridentate chelating mode through two N and one S atoms, forming metalla-rings. In the crystal, mol-ecules are connected through inversion centers via pairs of N-H⋯S inter-actions, building a one-dimensional hydrogen-bonded polymer along [0-1-1].

1-(2,4,6-Trioxo-1,3-diazinan-5-yl-idene)thio-semicarbazide.

The title mol-ecule, C(5)H(5)N(5)O(3)S, is approximately planar, with a maximum deviation from the mean plane through the non-H atoms of 0.182 (3) Šfor the amine N atom. In the crystal, mol-ecules are connected via N-H⋯O and N-H⋯S inter-actions, building a three-dimensional hydrogen-bonded network. Additionally, a weak intra-molecular N-H⋯O hydrogen bond is observed.

N'-[3-(Hy-droxy-imino)-butan-2-yl-idene]-4-methyl-benzene-1-sulfono-hydrazide.

In the title compound, C(11)H(15)N(3)O(3)S, the C-S-N(H)-N linkage is nonplanar, the torsion angle being 75.70 (12)°. The compound has two almost planar fragments linked to the S atom: the hydrazone-derivative fragment [(HONC(4)H(6))N-N(H)-] and the tolyl fragment (C(7)H(7)-) have maximum deviations from the mean plane through the non-H atoms of 0.0260 (10) and 0.0148 (14) Å, respectively. The two planar fragments make an inter-planar angle of 79.47 (5)°. In the crystal, mol-ecules are connected through inversion centers via pairs of N-H⋯O and O-H⋯N hydrogen bonds.