RESUMO

The 1-acyl thiourea family [R1C(O)NHC(S)NR2R3] exhibits the flexibility to incorporate a wide variety of substituents into their structure. The structural attributes of these compounds are intricately tied to the type and extent of substitution. In the case of 3-mono-substituted thioureas (R2=H), the conformational behavior is predominantly shaped by the presence of an intramolecular N-H ⋅ ⋅ ⋅ O=C hydrogen bond. This study delves into the structural consequences stemming from the inclusion of substituents possessing hydrogen-donor capabilities within four novel 1-acyl-3-mono-substituted thiourea derivatives. A comprehensive suite of analytical techniques, encompassing FTIR, Raman spectroscopy, multinuclear (1H and 13C) NMR spectroscopy, single-crystal X-ray diffraction, and supported by computational methods, notably NBO (Natural Bond Orbital) population analysis, Hirshfeld analysis, and QTAIM (Quantum Theory of Atoms in Molecules), was harnessed to scrutinize and characterize these compounds. In the crystalline state, these compounds exhibit an intricate interplay of intermolecular interactions, prominently featuring an expansive network of hydrogen bonds between the hydroxy (-OH) groups and the carbonyl and thiocarbonyl bonds within the 1-acyl thiourea fragment. Notably, the topological analysis underscores significant distinctions in the properties of the acyl thiourea fragment and the intramolecular >C=O ⋅ ⋅ ⋅ H-N bond when transitioning from the isolated molecule to the crystalline environment.

RESUMO

Osteosarcoma cancers are becoming more common in children and young adults, and existing treatments have low efficacy and a very high mortality rate, making it pressing to search for new chemotherapies with high efficacy and high selectivity index. Copper complexes have shown promise in the treatment of osteosarcoma. Here, we report the synthesis, characterization, and anticancer activity of [Cu(N-N-Fur)(NO3)(H2O)] complex where N-N-Fur is (E)-N'-(2-hydroxy-3-methoxybenzylidene)furan-2-carbohydrazide. The [Cu(N-N-Fur)(NO3)(H2O)] complex was characterized via X-ray diffraction and electron spin resonance (ESR), displaying a copper center in a nearly squared pyramid environment with the nitrate ligand acting as a fifth ligand in the coordination sphere. We observed that [Cu(N-N-Fur)(NO3)(H2O)] binds to DNA in an intercalative manner. Anticancer activity on the MG-63 cell line was evaluated in osteosarcoma monolayer (IC50 2D: 1.1 ± 0.1 µM) and spheroids (IC50 3D: 16.3 ± 3.1 µM). Selectivity assays using nontumoral fibroblast (L929 cell line) showed that [Cu(N-N-Fur)(NO3)(H2O)] has selectivity index value of 2.3 compared to cis-diamminedichloroplatinum(II) (CDDP) (SI = 0.3). Additionally, flow cytometry studies demonstrated that [Cu(N-N-Fur)(NO3)(H2O)] inhibits cell proliferation and conveys cells to apoptosis. Cell viability studies of MG-63 spheroids (IC50 = 16.3 ± 3.1 µM) showed that its IC50 value is 4 times lower than for CDDP (IC50 = 65 ± 6 µM). Besides, we found that cell death events mainly occurred in the center region of the spheroids, indicating efficient transport to the microtumor. Lastly, the complex showed dose-dependent reductions in spheroid cell migration from 7.5 to 20 µM, indicating both anticancer and antimetastatic effects.

Assuntos

Neoplasias Ósseas , Osteossarcoma , Criança , Humanos , Adulto Jovem , Cobre/farmacologia , Ligantes , Osteossarcoma/tratamento farmacológico

RESUMO

Eight Schiff bases, synthesized by the reaction of 4-aminoantipyrine with different cinnamaldehydes, were studied in the solid state by using vibrational spectroscopy (IR) and X-ray diffraction techniques. The analysis was extended to the solution phase through ultraviolet-vis, fluorescence spectroscopy, and cyclic voltammetry. Finally, the crystal structures of four compounds (3b, 3d, 3g, and 3h) were determined and studied. In addition to the experimental study, theoretical calculations using the semiempirical method PM6/ZDO were performed to understand better the compound's molecular properties, UV-vis, and infrared spectra. The primary difference is the angular conformation of the terminal phenyl rings around the corresponding linking C-N and C-C σ-bonds. Furthermore, as a result of extended bonding, the > C=N- azomethine group-containing Cpyr-N=(CH)-(CR)=(CH)-Cbz chain (with R=H for 3b, 3d, and 3h, and R=CH3 for 3g) is planar, nearly coplanar, with the mean plane of the pyrazole ring. Hirshfeld surface (HS) analysis was used to investigate the crystal packing and intermolecular interactions, which revealed that intermolecular C-H···O and C-H···N hydrogen bonds, π···π stacking, and C-H···π and C=O···π interactions stabilize the compounds. The energy contributions to the lattice energies of potential hydrogen bonds were primarily dispersive and repulsive. All derivatives were tested in vitro on LPS-stimulated mouse macrophages to assess their ability to suppress the LPS-induced inflammatory responses. Only a slight reduction in the level of NO production was found in activated macrophages treated with 3h. Additionally, the derivatives were tested for antimicrobial activity against several clinical bacteria and fungi strains, including three biofilm-forming microorganisms. Nevertheless, only Schiff base 3f showed interesting antibacterial activities with minimum inhibitory concentration (MIC) values as low as 15.6 µM against Enterobacter gergoviae. On the other hand, Schiff base 3f and, to a lesser extent, 3b and 3h showed antifungal activity against clinical isolates of Candida. The lowest MIC value was for 3f against Candida albicans (15.6 µM). It is interesting to note that the same Schiff bases exhibit the highest activity in both biological evaluations.

RESUMO

Chagas' disease (American Trypanosomiasis) is an ancient and endemic illness in Latin America caused by the protozoan parasite Trypanosoma cruzi. Although there is an urgent need for more efficient and less toxic chemotherapeutics, no new drugs to treat this disease have entered the clinic in the last decades. Searching for metal-based prospective antichagasic drugs, in this work, multifunctional Re(I) tricarbonyl compounds bearing two different bioactive ligands were designed: a polypyridyl NN derivative of 1,10-phenanthroline and a monodentate azole (Clotrimazole CTZ or Ketoconazol KTZ). Five fac-[Re(CO)3(NN)(CTZ)](PF6) compounds and a fac-[Re(CO)3(NN)(KTZ)](PF6) were synthesized and fully characterized. They showed activity against epimastigotes (IC50 3.48-9.42 µM) and trypomastigotes of T. cruzi (IC50 0.61-2.79 µM) and moderate to good selectivity towards the parasite compared to the VERO mammalian cell model. In order to unravel the mechanism of action of our compounds, two potential targets were experimentally and theoretically studied, namely DNA and one of the enzymes involved in the parasite ergosterol biosynthetic pathway, CYP51 (lanosterol 14-α-demethylase). As hypothesized, the multifunctional compounds shared in vitro a similar mode of action as that disclosed for the single bioactive moieties included in the new chemical entities. Additionally, two relevant physicochemical properties of biological interest in prospective drug development, namely lipophilicity and stability in solution in different media, were determined. The whole set of results demonstrates the potentiality of these Re(I) tricarbonyls as promising candidates for further antitrypanosomal drug development.

Assuntos

Antiprotozoários , Doença de Chagas , Compostos Organometálicos , Trypanosoma cruzi , Humanos , Doença de Chagas/tratamento farmacológico , Compostos Organometálicos/química , Antiprotozoários/química , Cetoconazol/química

RESUMO

A series of 2-(haloalkyl)-3-azidomethyl and 6-azido chromones has been synthetized, characterized and studied by theoretical (DFT calculations) and spectroscopic methods (UV-Vis, NMR). The crystal structure of 3-azidomethyl-2-difluoromethyl chromone, determined by X-ray diffraction methods, shows a planar framework due to extended π-bond delocalization. Its molecular packing is stabilized by F···H, N···H and O···H hydrogen bonds, π···π stacking and C-O···π intermolecular interactions. Moreover, AIM, NCI and Hirshfeld analysis evidenced that azido moiety has a significant role in the stabilization of crystal packing through weak intermolecular interactions, where analysis of electronic density suggested closed-shell (CS) interatomic interactions.

Assuntos

Ligação de Hidrogênio , Teoria da Densidade Funcional , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Difração de Raios X

RESUMO

Two new transition metal complexes with 1-methylimidazole (1-MeIm) and azide as ligands, namely, [Co(1-MeIm)4(N3)2] (1) and [Ni(1-MeIm)4(N3)2] (2), have been synthesized and characterized by IR, Raman, UV-Vis and XPS spectroscopy. Their crystal structures were solved by single-crystal X-ray diffraction. The supramolecular self-assembly of the two complexes is governed by non-classical C-H⋯N hydrogen bonds and C-H⋯π interactions. Lattice energies and intermolecular interaction energies for various molecular pairs are quantified using the PIXEL method. DFT computational studies to assess the binding energy through modern tools like non-covalent interaction (NCI plots) analysis and reduced density gradient (RDG) analysis have also been carried out. A detailed analysis of geometric descriptors revealed the existence of quasi-isostructural pairs or 'main-part' isostructuralism in a series formed by 1, 2, and a related cadmium complex, being more evident in the 1/2 pair. DFT studies using theoretical models have been used to disclose the relative importance of the H-bond and C-H⋯π noncovalent interactions. Magnetic measurements for compound 1 show weak ferrimagnetic coupling between adjacent M(II) centers, mediated by H-bonding and C-H⋯π non-covalent interactions.

RESUMO

Diverse models of intramolecular charge transfer (ICT) have been proposed for interpreting the origin of the charge-transfer (CT) state in donor-acceptor (D-A) dyes. However, a large variety of fused-heterocyclic dyes containing a pseudo-aromatic ring in the rigid structure have shown to be incompatible with them. To approximate a solution within the ICT concept, we reported a novel ICT model called partially aromatized intramolecular charge transfer (PAICT). PAICT involves the generation of a CT state from an ICT that occurred within a pre-excited D-A fused-heterocyclic structure possessing a pseudo-aromatic or unstable aromatic ring as the acceptor moiety. The model was proposed from the multiple-emissive mesomeric D-A N1-aryl-2-(trifluoromethyl)benzo[b][1,8]naphthyridin-4(1H)-one, whose excited mesomeric states, which are defined by the aromatic and pseudo-aromatic forms of the pyrindin-4(1H)-one ring, led to a common partial aromatized CT state upon excitation via PAICT. The latter was supported through theoretical calculations on the excited mesomeric states, one-dimensional (1D) and two-dimensional (2D) excitation-emission measurements in different solvents, and the detection of three excited states by lifetime measurements upon 370 nm excitation. The existence of mesomerism was supposed from: (i) two overlapping bands at 370-390 (or 400-420 nm) in UV-vis spectra, (ii) the direct interaction between the pyridinic nitrogen of one molecule and the carbonylic oxygen of the other found in the solid state and, (iii) the detection of three excited states by lifetime measurements. The PAICT opens new perspectives for interpreting the charge-transfer phenomenon in fused-heterocyclic dyes, in particular, those containing a pseudo-aromatic or unstable aromatic ring as an acceptor moiety.

Assuntos

Corantes/química , Solventes

RESUMO

We report here the synthesis, crystal structure, characterization and anticancer activity of a copper(ii)-hydrazone complex, [Cu(MeBHoVa)(H2O)2](NO3) (for short, CuHL), against human breast cancer cells on monolayer (2D) and spheroids/mammospheres (3D). The solid-state molecular structure of the complex has been determined by X-ray diffraction methods. The conformational space was searched and geometries were optimized both in the gas phase and including solvent effects by computational methods based on DFT. The compound has been characterized in the solid state and in solution by spectroscopic (FTIR, Raman, UV-vis) methods. The results were compared with those obtained for the hydrazone ligand and complemented with DFT calculations. Cell viability assays on MCF7 (IC50(CuHL) = 1.7 ± 0.1 µM, IC50(CDDP) = 42.0 ± 3.2 µM) and MDA-MB-231 (IC50(CuHL) = 1.6 ± 0.1 µM, IC50(CDDP) = 131.0 ± 18 µM) demonstrated that the complex displays higher antitumor activity than cisplatin (CDDP) on 2D and 3D human breast cancer cell models. Molecular docking and molecular dynamics simulations showed that CuHL could interacts with DNA, inducing a significant genotoxic effect on both breast cancer cells from 0.5 to 1 µM. On the other hand, CuHL increases the ROS production and induces cell programmed death on breast cancer cells at very low micromolar concentrations (0.5-1.0 µM). Moreover, the compound decreased the amount of breast CSCs on MCF7 and MDA-MB-231 cells reducing the percentage of CD44+/CD24-/low cells from 0.5 to 1.5 µM. In addition, CuHL overcame CDDP with an IC50 value 65-fold lower against breast multicellular spheroids ((IC50(CuHL) = 2.2 ± 0.3 µM, IC50(CDDP) = 125 ± 4.5 µM)). Finally, CuHL reduced mammosphere formation capacity, hence affecting the size and number of mammospheres and showing that the complex exhibits antitumor properties on monolayer (2D) and spheroids (3D) derived from human breast cancer cells.

Assuntos

Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Complexos de Coordenação/farmacologia , Cobre/farmacologia , Hidrazonas/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/química , Cobre/química , Dano ao DNA , Feminino , Humanos , Hidrazonas/química , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mutagênicos/química , Mutagênicos/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Esferoides Celulares/efeitos dos fármacos

RESUMO

The compound 1,3,3-trimethyl-2-oxabicyclo[2.2.2]octan-9-ol (9-hydroxyeucaliptol) has been prepared and characterized by single-crystal X-ray diffraction analysis, infrared, Raman, and UV-visible spectroscopies. The molecular geometry of the title compound was also investigated theoretically by density functional theory (DFT) calculations to compare with the experimental data. The substance crystallizes in the trigonal crystal system, space group P32 with Z = 9 molecules per unit cell. There are three independent molecules in the crystal asymmetric unit having the same chirality and showing some differences in the orientation of the H-atom of the hydroxyl group. The crystal structure of 9-hydroxyeucaliptol shows that the hydroxyl group presents an anti-conformation with respect to the O-atom of the ether group. The crystal packing of 9-hydroxyeucaliptol is stabilized by intermolecular O-H···O hydrogen bonds involving the hydroxyl groups of different molecules, which play a decisive role in the preferred conformation adopted in solid state. The intermolecular interactions observed in solid state were also studied through the Hirshfeld surface analysis and quantum theory of atoms in molecules (QTAIM) approaches. Energy framework calculations have also been carried out to analyze and visualize the topology of the supramolecular assembly, and the results indicate a significant contribution from electrostatic energy over the dispersion.

RESUMO

The reaction of N-phenyl-1-(pyridin-2-yl)methanimine with copper chloride dihydrate produced the title neutral complex, [CuCl2(C12H10N2)(H2O)]·H2O. The CuII ion is five-coordinated in a distorted square-pyramidal geometry, in which the two N atoms of the bidentate Schiff base, as well as one chloro and a water mol-ecule, form the irregular base of the pyramidal structure. Meanwhile, the apical chloride ligand inter-acts through a strong hydrogen bond with a water mol-ecule of crystallization. In the crystal, mol-ecules are arranged in pairs, forming a stacking of symmetrical cyclic dimers that inter-act in turn through strong hydrogen bonds between the chloride ligands and both the coordinated and the crystallization water mol-ecules. The mol-ecular and electronic structures of the complex were also studied in detail using EPR (continuous and pulsed), FT-IR and Raman spectroscopy, as well as magnetization measurements. Likewise, Hirshfeld surface analysis was used to investigate the inter-molecular inter-actions in the crystal packing.

RESUMO

The strange tautomeric equilibrium behavior exhibited by a new o-hydroxyphenyl diazepine derivative when the compound is analyzed both in solution and solid state opens the structural study of the enol-imino-keto-enamine forms and the influence of the intermolecular interactions in their equilibrium. The expected enol-imino form, in which the enol is part of a phenyl system and a strong O-H···N intramolecular hydrogen bond is established, results the most stable tautomer in gas phase (theoretical calculations) and was detected by NMR spectroscopy when the compound was dissolved in aprotic solvents. Nevertheless, the keto-enamine form ,in which the keto group integrates a cyclohexadienone moiety and the aromaticity of the phenol is lost, was the only tautomer in the crystal lattice according to single-crystal X-ray diffraction, vibrational spectroscopy, and diffuse reflectance results. The last form was also found as the main tautomer in UV-vis and NMR spectroscopy when a protic solvent was employed.

RESUMO

Isatin in a solution of dry N,N-dimethylformamide/NaClO4 is electroreduced in the presence of CH3I. N-methylisatin (NMI) is obtained in quantitative molar yield and high current efficiency by controlled potential electrolysis (CPE). NMI and N-methylisatoic anhydride are the reaction products when CPE is performed in the absence of CH3I, but adding it once the CPE was completed. The water effect on the identity and yield of the reaction product(s) is investigated. Reaction pathways are proposed.

RESUMO

An unpredicted fourfold screw N-H...O hydrogen bond C(4) motif in a primary dicarboxamide (trans-cyclohexane-1,4-dicarboxamide, C8H14N2O2) was investigated by single-crystal X-ray diffraction and IR and Raman spectroscopies. Electron-density topology and intermolecular energy analyses determined from ab initio calculations were employed to examine the influence of weak C-H...O hydrogen-bond interactions on the peculiar arrangement of molecules in the tetragonal P43212 space group. In addition, the way in which the co-operative effects of those weak bonds might modify their relative influence on molecular packing was estimated from cluster calculations. Based on the results, a structural model is proposed which helps to rationalize the unusual fourfold screw molecular arrangement.

RESUMO

A new losartan [2-butyl-5-chloro-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol zinc(II) complex [Zn(Los)Cl], was synthesized and characterized. The crystal structure was determined by x-ray diffraction methods. When aqueous solutions of the ligand and the metal were mixed, the known and more soluble powder [Zn(Los)2].3H2O (ZnLos) complex has been obtained. The interactions with phosphatases showed a concerted mechanism displayed by the Zn ions and ZnLos up to 500 µM concentration: a decrease of the acid phosphatase (AcP) associated with an increase in the alkaline phosphatase (ALP) activities. The complex and ZnSO4 showed a cytotoxic behavior on human lung A549 cancer cell line at concentrations higher than 75 µM with reactive oxygen species (ROS) generation and GSH (and GSH/GSSG ratio) depletion. Apoptotic cells were observed using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) method, a mechanism accompanied by upregulation of BAX protein, downregulation of Bcl-XL and release of caspase-3. The BAX/Bcl-XL ratio was found to be significantly higher in cells exposure to ZnLos than cells treated with ZnSO4, in agreement with the higher apoptotic percentage of cells found for the complex. Cell death was found to be produced by apoptosis and no necrosis has been observed. On the contrary, losartan exerted low effects on phosphatases, produced some reduction of cancer cell viability (concentrations > 250 µM, number of apoptotic cells similar to the basal) with low ROS depletion, without alteration of the GSH/GSSG and low BAX/Bcl-XL ratios. In the MRC-5, normal lung fibroblasts cell line only ZnSO4 at concentrations higher than 200 µM displays cytotoxic effects. Graphical abstract Interaction of Zn with losartan. Activation of intrinsic apoptotic signaling pathway in lung cancer cells and effects on alkaline and acid phosphatases.

Assuntos

Fosfatase Ácida/metabolismo , Fosfatase Alcalina/metabolismo , Apoptose/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Losartan/farmacologia , Zinco/farmacologia , Células A549 , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Caspase 3/metabolismo , Complexos de Coordenação/química , Glutationa/metabolismo , Humanos , Losartan/química , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Zinco/química , Proteína X Associada a bcl-2/metabolismo , Proteína bcl-X/metabolismo

RESUMO

Coumarins (2H-chromen-2-one) are oxygen-containing heterocyclic compounds that belong to the benzopyranones family. In this work we have synthesized different coordination complexes with coumarin-3-carboxylic acid (HCCA), o-phenanthroline (phen) and zinc(II). In the reported [Zn(CCA)2(H2O)2] complex, coumarin-3-carboxylate (CCA) is acting as a bidentate ligand while in the two prepared complexes, [Zn(phen)3]CCA(NO3) (obtained as a single crystal) and [Zn(CCA)2phen].4H2O, CCA is acting as a counterion of the complex cation [Zn(phen)3]+2 or coordinated to the metal center along with phen, respectively. These compounds were characterized on the basis of elemental analysis and thermogravimetry. NMR, FTIR and Raman spectroscopies of the compounds and the CCA potassium salt (KCCA) allow to determine several similarities and differences among them. Finally, their behavior against alkaline phosphatase enzyme and their antimicrobial activities were also measured.

Assuntos

Anti-Infecciosos/farmacologia , Complexos de Coordenação/química , Cumarínicos/química , Fenantrolinas/química , Compostos de Zinco/química , Fosfatase Alcalina/química , Fosfatase Alcalina/metabolismo , Anti-Infecciosos/química , Complexos de Coordenação/farmacologia , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman

RESUMO

Azilsartan is the eighth approved member of angiotensin II receptor blockers for hypertension treatment. Considering that some drugs have additional effects when administered, we studied its effects and mechanisms of action on a human lung cancer cell line A549. We have also modified the structure of the drug by complexation with Zn(II) cation and assayed the anticancer effect. The crystal structure of the new binuclear Zn(II) complex, for short [Zn2(azil)2(H2O)4]·2H2O (ZnAzil), was determined by X-ray diffraction methods. The zinc ions are bridged by azilsartan ligands through their carboxylate oxygen and oxadiazol nitrogen atoms. The compounds were examined for their cytotoxic effects against human lung fibroblast (MRC5) and human lung cancer (A549) cell lines. Azilsartan displayed low cytotoxic effects at 150 µM concentrations in A549 human lung cancer cells but the higher effect measured for the Zn complex suggested that this compound may act as an anticancer agent. An apoptotic oxidative stress mechanism of action via the mitochondrial-dependent intrinsic pathway has been determined. Besides, the compounds exerted weak cytotoxic effects in the normal lung related cell line MRC5. Binding constants of the complex formed between each compound and bovine serum albumin (BSA) are in the intermediate range, hence suggesting that azilsartan and ZnAzil could be bonded and transported by BSA.

Assuntos

Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Oxidiazóis/farmacologia , Células A549 , Antineoplásicos/química , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Benzimidazóis/química , Fibroblastos/efeitos dos fármacos , Humanos , Modelos Moleculares , Necrose/induzido quimicamente , Necrose/patologia , Oxidiazóis/química , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , Soroalbumina Bovina/química , Difração de Raios X , Zinco/química

RESUMO

Two lamotriginium salts, namely lamotriginium crotonate [systematic name: 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazin-2-ium but-2-enoate, C9H8Cl2N5+·C4H5O2-, (III)] and lamotriginium salicylate [systematic name: 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazin-2-ium 2-hydroxybenzoate ethanol monosolvate, C9H8Cl2N5+·C7H5O3-·C2H5OH, (IV)] present extremely similar centrosymmetric hydrogen-bonded A...L...L...A packing building blocks (L is lamotriginium and A is the anion). The fact that salicylate salt (IV) is (ethanol) solvated, while crotonate salt (III) is not, has a profound effect on the way these elemental units aggregate to generate the final crystal structure. Possible reasons for this behaviour are analyzed and the hypothesis raised checked against similar structures in the literature.

RESUMO

In the current study the ability of copper complex to exert multiple biological activities is combined with the pharmacological action of sertraline (SerH2Cl, antidepressant drug). The hydrated and anhydrous forms of the tetrachlorocuprate(II) salts, namely (SerH2)2[CuCl4]·½H2O and (SerH2)2[CuCl4], were synthesized and characterized by physicochemical methods. The crystal structures were determined by X-ray diffraction methods. The hydrate complex crystallizes in the monoclinic P21 space group with a=8.0807(2) Å, b=36.2781(8) Å, c=12.6576(3) Å, ß=95.665(2)°, and Z=4 molecules per unit cell and the un-hydrate in P21 with a=13.8727(6) Å, b=7.5090(3) Å, c=18.618(1) Å, ß=104.563(6)°, and Z=2. It has been suggested that Cu(II) ions might be critical in the development of mood disorders, showed potent biocidal activity, and also acted as analgesic adjuvant. To improve sertraline efficiency, the antidepressant and analgesic activities of the complex have been assessed in rats denoting a marked synergistic effect. Antithyroid and antimicrobial activities were also evaluated. Because depressive disorders and hyperthyroidism diseases led to an oxidative stress state, antioxidant capability has also been tested. The complex behaved as a good superoxide radical scavenger (IC50=6.3×10-6M). The ability of the complex to act as bromoperoxidase mimic was assessed. A pseudo-first order constant of k=0.157±0.007min-1 has been determined. The complex evidences promising biological-pharmacological activities and the albumin binding studies showed a Kb of 2.90×103M-1 showing an improvement in the uptake of sertraline by albumin at 8h incubation (time required for effective interaction of sertraline with the protein).

Assuntos

Analgésicos , Anti-Infecciosos , Antidepressivos , Complexos de Coordenação , Cobre , Sertralina , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antidepressivos/síntese química , Antidepressivos/química , Antidepressivos/farmacologia , Bovinos , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cobre/química , Cobre/farmacologia , Masculino , Ratos , Ratos Wistar , Sertralina/química , Sertralina/farmacologia

RESUMO

To improve the antidepressant action of sertraline a new salt with coumarin-3-carboxylate anion (SerH-CCA) has been synthesized by two different methods and characterized by FTIR spectroscopy and structural determinations by X-ray diffraction methods. The new salt is stabilized by strong intermolecular H-bonds involving the protonated amine group of SerH and the deprotonated carboxylate group of CCA. These findings can be correlated with the interpretation of the infrared spectrum. The salt, sertraline (SerHCl) and the sodium salt of coumarin-3-carboxylate (NaCCA) were orally administered male Wistar rats (10 mg/kg, based on sertraline). Rats were evaluated in separate groups by means of the forced swimming (FST). SerH-CCA produced antidepressant effects in a magnitude that exceeded SerHCl individual effects. None of these treatments affected activity levels by the open field OFT tests. We have also determined that the ion pair also improve the binding to bovine serum albumin (BSA) of the drug but retain its antimicrobial activity. It is reasonable to conclude that the replacement of chloride anion by a large organic anion in sertraline strengthens the pharmacological action of the native drug, binding to BSA with higher activity and retaining the antimicrobial activity of the antidepressant compound.

Assuntos

Antidepressivos/química , Antidepressivos/farmacocinética , Cumarínicos/química , Sertralina/química , Sertralina/farmacocinética , Animais , Anti-Infecciosos/química , Anti-Infecciosos/farmacocinética , Anti-Infecciosos/farmacologia , Antidepressivos/farmacologia , Disponibilidade Biológica , Cristalização/métodos , Depressão/tratamento farmacológico , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar , Sertralina/farmacologia , Natação/fisiologia , Difração de Raios X/métodos

RESUMO

Five Schiff bases obtained from condensation of 4-methoxybenzohydrazide with related aldehydes, namely o-vanillin, vanillin, 5-bromovanillin, 5-chlorosalicylaldehyde and 5-bromosalicylaldehyde were prepared. A detailed structural and spectroscopic study is reported. The crystal structures of four members of the family were determined and compared with one another. The hydrazones obtained from 5-chlorosalicylaldehyde and 5-bromosalicylaldehyde resulted to be isomorphic to each other. The solid-state structures are stabilized by intra-molecular O-H⋯N interactions in salicylaldehyde derivatives between the O-H moiety from the aldehyde and the hydrazone nitrogen atom. All crystals are further stabilized by inter-molecular H-bonds mediated by the crystallization water molecule. A comparative analysis between experimental and theoretical results is presented. The conformational space was searched and geometries were optimized both in gas phase and including solvent effects. The structure is predicted for the compound for which the crystal structure was not determined. Infrared and electronic spectra were measured and assigned with the help of data obtained from computational methods based on the Density Functional Theory.

Assuntos

Aldeídos/química , Benzaldeídos/química , Hidrazinas/química , Hidrazonas/química , Bases de Schiff/química , Espectroscopia de Infravermelho com Transformada de Fourier , Bromo/química , Cristalografia por Raios X , Elétrons , Etanol/química , Ligação de Hidrogênio , Cetonas/química , Ligantes , Conformação Molecular , Processamento de Sinais Assistido por Computador , Software , Espectrofotometria Infravermelho , Temperatura , Difração de Raios X