Structure-activity relationship and cytotoxicity of the new thiosemicarbazide derivatives and their Cu(II) complexes against prostate and melanoma cancer cells.

In this study, eighteen new ligands (B1-B18) containing a thiosemicarbazide core were synthesized and characterized in terms of physicochemical properties, molecular docking and in vitro biological activity. The structures of eleven ligands were investigated using X-Ray diffraction and Hirschfeld Surface analysis. To study the structure-activity relationship, the organic ligands contained pyridin-2-ylmethyl, pyridin-3-ylmethyl or pyridin-4-ylmethyl moieties and various substituents. Their pharmakokinetic profiles and molecular docking results suggest high potential as new drug candidates. The complexing ability of the selected organic ligands was also evaluated, yielding five new Cu(II) complexes (Cu(B1)Cl2, Cu(B4)Cl2, Cu(B10)Cl2, Cu(B17)Cl2, Cu(B18)Cl2). The obtained results suggest the formation of the polymeric structures. All organic ligands and Cu(II) complexes were tested for anticancer activity against prostate and melanoma cancer cells (PC-3, DU-145, LNCaP, A375, G-361, SK-MEL-28) and normal fibroblasts (BJ), as well as antimicrobial activity against six selected bateria strains. Among B1-B18 compounds, B3, B5, B9, B10, B12 and B14 exhibited cytotoxic activity. The studied Cu(II) complexes were in general more active, with Cu(B1)Cl2 exhibiting antincancer activity agains all three prostate cancer cells and Cu(B10)Cl2 reaching the IC50 value equal to 88 µM against G-361 melanoma cells. Several compounds also exhibited antimicrobial activity against gram-positive and gram-negative bacteria. It was found that the type of specific substituents, especially the presence of -chloro and -dichloro substituents had a greated impact on the cytotoxicity than the position of the nitrogen atom in the pyridylacetyl moiety.

Novel phenoxyacetylthiosemicarbazide derivatives as novel ligands in cancer diseases.

Numerous epidemiological studies report an increased risk of developing prostate cancer in patients with melanoma and an increased risk of developing melanoma in patients with prostate cancer. Based on our previous studies demonstrating the high anticancer activity of thiosemicarbazides with a phenoxy moiety, we designed nineteen phenoxyacetylthiosemicarbazide derivatives and four of them acting as potential dual-ligands for both cancers. All of the compounds were characterized by their melting points and 1H, 13C NMR and IR spectra. For selected compounds, X-ray investigations were carried out to confirm the synthesis pathway, identify the tautomeric form and intra- and intermolecular interaction in the crystalline state. The conformational preferences and electronic structure of molecules were investigated by theoretical calculation method. Lipophilicity of compounds (log kw) was determined using isocratic reversed phase/high pressure liquid chromatography RP-18. For the obtained compounds, in vitro tests were carried out on four melanoma cell lines (A375, G-361, SK-MEL2, SK-MEL28), four prostate cancer cell lines (PC-3, DU-145, LNCaP, VcaP) and a normal human fibroblast cell line (BJ). The most active compounds turned out to be F6. Cell cycle analysis, apoptosis detection, CellROX staining and mitochondrial membrane potential analysis were performed for the most sensitive cancer cells treated with most active compounds. DSC analysis was additionally performed for selected compounds to determine their purity, compatibility, and thermal stability. The process of prooxidation was proposed as a potential mechanism of anticancer activity.

Polymer microspheres modified with pyrazole derivatives as potential agents in anticancer therapy - Preliminary studies.

The methods of fighting cancer are far from ideal, therefore it is necessary to search for innovative and effective drugs. In our work, we present pyrazole derivatives and their modifications with polymer microspheres as potential anticancer agents. Molecular and crystal structures of pyrazole derivatives were determined an X-ray analysis and characterized by theoretical calculations. Modifications of cross-linked polymer microspheres with pyrazole derivatives were made on the basis of divinylbenzene and glycidyl methacrylate. The in vitro antiproliferative activity of the pyrazole derivatives and their modified microspheres was assessed against a normal cell line, namely monkey epithelial renal cells (GMK) and cancer cell lines, such as human hepatocellular carcinoma cell line (HepG2), human breast adenocarcinoma cell line (MCF-7) as well as human lung adenocarcinoma cell line (A549), using the MTT assay. All the tested pyrazole derivatives and the polymer microspheres modified by them showed antiproliferative activity in vitro. Two of the modified substances showed the greatest ability to inhibit divisions of all cancer cells. In order to determine a potential target, molecular docking was performed. In silico studies carried out with the use of the human EphB1 receptor revealed that the analyzed compounds bound to the EphB1 binding site, and the compounds with the highest antiproliferative activity showed a better fit to the active site.

Influence of Complexation of Thiosemicarbazone Derivatives with Cu (II) Ions on Their Antitumor Activity against Melanoma Cells.

A series of thiosemicarbazone derivatives was prepared and their anti-tumor activity in vitro was tested. The X-ray investigation performed for compounds T2, T3 and T5 confirmed the synthesis pathway and assumed molecular structures of analyzed thiosemicarbazones. The conformational preferences of the thiosemicarbazone system were characterized using theoretical calculations by AM1 method. Selected compounds were converted into complexes of Cu (II) ions. The effect of complexing on anti-tumor activity has been investigated. The copper(II) complexes, with Schiff bases T1, T10, T12, T13, and T16 have been synthesized and characterized by chemical and elemental analysis, FTIR spectroscopy and TGA method. Thermal properties of coordination compounds were studied using TG-DTG techniques under dry air atmosphere. G361, A375, and SK-MEL-28 human melanoma cells and BJ human normal fibroblast cells were treated with tested compounds and their cytotoxicity was evaluated with MTT test. The compounds with the most promising anti-tumour activity were then selected and their cytotoxicity was verified with cell cycle analysis and apoptosis/necrosis detection. Additionally, DNA damages in the form of a basic sites presence and the expression of oxidative stress and DNA damage response genes were evaluated. The obtained results indicate that complexation of thiosemicarbazone derivatives with Cu (II) ions improves their antitumor activity against melanoma cells. The observed cytotoxic effect is associated with DNA damage and G2/M phase of cell cycle arrest as well as disorders of the antioxidant enzymes expression.

Synthesis, Structural Characterization, and Biological Activity of New Pyrazolo[4,3-e][1,2,4]triazine Acyclonucleosides.

A series of new pyrazolo[4,3-e][1,2,4]triazine acyclonucleosides 2-5 and 8 were prepared and evaluated for their anticancer activity against human cancer cell lines (MCF-7, K-562) and CDK2/E, as well as Abl protein kinases inhibitors. Lipophilicity of the compounds was determined using C-18 and immobilized artificial membrane (IAM) chromatography. In order to confirm the molecular structures and synthesis pathway of new acyclonucleosides, X-ray analysis was performed for model compound 3. Theoretical calculations at the DFT/B3LYP/6-311++G(d,p) level were used for the characterization of electronic structures of 1-8. The potential antiviral activity of acyclonucleosides 2-8 was tested in silico using molecular docking method.

New Application of 1,2,4-Triazole Derivatives as Antitubercular Agents. Structure, In Vitro Screening and Docking Studies.

A series of 1,2,4-triazole derivatives were synthesized and assigned as potential anti-tuberculosis substances. The molecular and crystal structures for the model compounds C1, C12, and C13 were determined using X-ray analysis. The X-ray investigation confirmed the synthesis pathway and the assumed molecular structures for analyzed 1,2,4-triazol-5-thione derivatives. The conformational preferences resulting from rotational degrees of freedom of the 1,2,4-triazole ring substituents were characterized. The lipophilicity (logP) and electronic parameters as the energy of frontier orbitals, dipole moments, NBO net charge distribution on the atoms, and electrostatic potential distribution for all structures were calculated at AM1 and DFT/B3LYP/6-311++G(d,p) level. The in vitro test was done against M. tuberculosis H37Ra, M. phlei, M. smegmatis, and M. timereck. The obtained results clearly confirmed the antituberculosis potential of compound C4, which turned out to be the most active against Mycobacterium H37Ra (MIC = 0.976 µg/mL), Mycobaterium pheli (MIC = 7.81 µg/mL) and Mycobacerium timereck (62.6 µg/mL). Satisfactory results were obtained with compounds C8, C11, C14 versus Myc. H37Ra, Myc. pheli, Myc. timereck (MIC = 31.25-62.5 µg/mL). The molecular docking studies were carried out for all investigated compounds using the Mycobacterium tuberculosis cytochrome P450 CYP121 enzyme as molecular a target connected with antimycobacterial activity.

1,2,4-Triazine Sulfonamides: Synthesis by Sulfenamide Intermediates, In Vitro Anticancer Screening, Structural Characterization, and Molecular Docking Study.

In this study, we synthesized novel sulfonamides with a 1,2,4-triazine moiety according to pharmacophore requirements for biological activity. All the synthesized compounds were tested in vitro to verify whether they exhibited anticancer activity against the human breast cancer cell lines MCF-7 and MDA-MB-231. Among them, two most active ones, having IC50 values of 50 and 42 µM, respectively, were found to show higher anticancer activity than chlorambucil used as the reference in the in vitro tests. In addition, two other compounds, which had IC50 values of 78 and 91 µM, respectively, exhibited a similar level of activity as chlorambucil. X-ray analysis carried out for two of the compounds confirmed their synthesis pathway as well as their assumed molecular structures. Furthermore, a conformational analysis was performed, and electronic parameters of molecules were characterized using theoretical calculations at AM1 and DFT level. Moreover, molecular docking revealed the mode of binding of the investigated 1,2,4-triazine sulfonamides with the human estrogen receptor alpha (ERα).

Synthesis, In Vitro Screening and Docking Studies of New Thiosemicarbazide Derivatives as Antitubercular Agents.

A series of thiosemicarbazide derivatives was designed and synthesized by reaction of carboxylic acid hydrazide with isothiocyanates. The molecular structures of the investigated thiosemicarbazides were confirmed and characterized by spectroscopic analysis. The conformational preference of carbonylthiosemicarbazide chain and intra- and intermolecular interactions in the crystalline state were characterized using X-ray analysis. The antituberculosis activity of the target compounds were tested in vitro against four Mycobacterium strains: M. H37Ra, M. phlei, M. smegmatis, M. timereck. The most active compounds were those with 2-pyridine ring. They exhibited lower minimal inhibitory concentration (MIC) values in the range 7.81⁻31.25 µg/mL in comparison to the other isomers. Compound 5 had activity against M. smegmatis at a concentration of 7.81 µg/mL whereas compound 2 had activity against all tested strains at a concentration of 15.625 µg/mL. The molecular docking studies were performed for investigated compounds using the Mycobacterium tuberculosis glutamine synthetase MtGS as their molecular target.

Discovery of nitroaryl urea derivatives with antiproliferative properties.

A series of urea derivatives bearing nitroaryl moiety has been synthesized and assayed for their potential antiproliferative activities. Some of the tested compounds displayed activity in RK33 laryngeal cancer cells and TE671 rhabdomyosarcoma cells while being generally less toxic to healthy HSF human fibroblasts cells. One compound was demonstrated to be a moderate CDK2 inhibitor with IC50 = 14.3 µM. Its structure was solved by an X-ray crystallography and molecular modelling was performed to determine structure-activity relationship. Obtained compounds constitute novel structures and generally demonstrated greater cytotoxicity in comparison to cisplatin. This study offers new structural motifs with potential for further development.

New approaches to the synthesis of sildenafil analogues and their enzyme inhibitory activity.

In the search for new biologically active chemotypes, several sildenafil analogs were prepared and characterized. The presence of the pyrazolo[4,3-e][1,2,4]triazine core is thought to be of interest for the enzyme inhibitory activity of these compounds. The designed derivatives incorporating the sildenafil scaffold were assayed as carbonic anhydrase inhibitors, and for their cytotoxic activity against MCF-7 and K562 cell lines. The X-ray analysis of one of these model compounds was performed and its crystal structure is described/compared to that of sildenafil.

Synthetic approaches for sulfur derivatives containing 1,2,4-triazine moiety: their activity for in vitro screening towards two human cancer cell lines.

A series of sulfur 1,2,4-triazine derivatives were prepared and evaluated as anticancer compounds for two human breast cancer cell lines (MCF-7, MDA-MB-231) with some of them acting as low micromolar inhibitors. Evaluation of the cytotoxicity using a 3-(4,5-dimethylthiazol-2-yl)-3,5-diphenyltetrazolium bromide (MTT) assay, the inhibition of [(3)H]thymidine incorporation into DNA, and collagen synthesis inhibition demonstrated that these products exhibit cytotoxic effects on these breast cancer cell lines in vitro. The most effective were disulfide and sulfenamide compounds with two valence sulfur atoms. A structure-activity relationship study was performed using X-ray analysis and theoretical calculations at an ab initio density functional theory (DFT) level.

Synthesis, Structural Studies and Molecular Modelling of a Novel Imidazoline Derivative with Antifungal Activity.

Six novel imidazoline derivatives were synthesized and tested in antifungal assays. One of the compounds, N-cyclohexyl-2-imino-3-(4-nitrophenyl)imidazolidine-1-carboxamide showed moderate activity against several clinical strains of Candida albicans. Its structure was solved by X-ray crystallography and its mode of action was deduced using molecular modelling. It was found to be similar to that of fluconazole. The potential for further optimization including SAR of the compound is briefly discussed.

Structural studies, homology modeling and molecular docking of novel non-competitive antagonists of GluK1/GluK2 receptors.

Non-competitive ligands of kainate receptors have focused significant attention as medicinal compounds because they seem to be better tolerated than competitive antagonists and uncompetitive blocker of these receptors. Here we present structural studies (X-ray structure determination, NMR and MS spectra) of novel indole-derived non-competitive antagonists of GluK1/GluK2 receptors, homology models of GluK1 and GluK2 receptors based on novel AMPA receptor template as well as molecular docking of ligands to their molecular targets. We find that the allosteric site is in the receptor transduction domain, in one receptor subunit, not between the two subunits as it was indicated by our earlier studies.

Synthesis and structural characterizations of three carbonyl(α-diimine)hydrido(triphenylphosphine)ruthenium(II) complexes with derivatives of 1,10-phenanthroline.

Three new ruthenium(II) polypyridyl complexes containing α-diimine ligands, namely, carbonylhydrido(1,10-phenanthroline-κ2N,N)bis(triphenylphosphine-κP)ruthenium(II) hexafluorophosphate, [RuH(C12H8N2)(C18H15P)2(CO)]PF6, carbonylhydrido(2,9-dimethyl-1,10-phenanthroline-κ2N,N)bis(triphenylphosphine-κP)ruthenium(II) hexafluorophosphate, and carbonylhydrido(4,7-dimethyl-1,10-phenanthroline-κ2N,N)bis(triphenylphosphine-κP)ruthenium(II) hexafluorophosphate, both [RuH(C14H12N2)(C18H15P)2(CO)]PF6, were synthesized and characterized by spectroscopic and X-ray diffraction methods. In these complexes, the ruthenium(II) ion adopts a distorted octahedral geometry. There are no intermolecular hydrogen bonds in the crystal structures of the analysed complexes and Hirshfeld surface analysis showed that the H...H contacts constitute a high percentage, close to 50%, of the intermolecular interactions.

Synthesis of novel isothiazolopyridines and their in vitro evaluation against Mycobacterium and Propionibacterium acnes.

In this paper we describe synthesis, structures and some physicochemical properties of 20 isothiazolopyridines 8-13 substituted differently into an isothiazole ring as well as their in vitro antibacterial assays against Mycobacterium tuberculosis H37Rv, Mycobacterium fortuitum PCM 672 and Propionibacterium acnes PCM 2400. Compound 13a was found to be the most active derivative against M. tuberculosis H37Rv, demonstrating 100% growth inhibition of microorganisms in the primary screen (minimum inhibitory concentration [MIC] 6.25µg/mL). Nineteen of the prepared compounds were evaluated against M. fortuitum PCM 672 and P. acnes PCM 2400 and only compounds 9 and 12d exhibited excellent activity against individual strains of microorganisms with MIC90 <1µg/mL. The inhibitory action of the remaining isothiazolopyridines towards the tested strains of the microorganism was low, absent, or a non-linear correlation prohibited accurate determination of MIC values. Unexpectedly, seven of the remaining isothiazolopyridines tested against M. fortuitum and P. acnes stimulated growth of the microorganisms in the range 10-50% or even more (10b) under experimental conditions.

3-Benzyl-4-ethyl-1H-1,2,4-triazole-5(4H)-thione.

The title compound, C(11)H(13)N(3)S, exists in the 5-thioxo tautomeric form. The benzene ring exhibits disorder with a refined ratio of 0.77 (2):0.23 (2) for components A and B with a common bridgehead C atom. The 1,2,4-triazole ring is essentially planar, with a maximum deviation of 0.002 (3) Šfor the benzyl-substituted C atom, and forms dihedral angles of 88.94 (18) and 86.56 (49)° with the benzene rings of components A and B, respectively. The angle between the plane of the ethyl chain and the mean plane of 1,2,4-triazole ring is 88.55 (15)° and this conformation is stabilized by an intra-molecular C-H⋯S contact. In the crystal, pairs of N-H⋯S hydrogen bonds link mol-ecules into inversion dimers. π-π inter-actions are observed between the triazole and benzene rings, with centroid-centroid separations of 3.547 (4) and 3.544 (12) Šfor components A and B, and slippages of 0.49 (6) and 0.58 (15) Å, respectively.

N-Substituted 2-(Benzenosulfonyl)-1-Carbotioamide Derivatives Exert Antimicrobial and Cytotoxic Effects via Aldehyde Dehydrogenase Pathway: Synthesis, In Silico and In Vitro Studies.

A series of N-Substituted 2-(benzenosulfonyl)-1-carbotioamide derivatives (WZ1-WZ4) were synthesized and characterized using spectral methods. A comprehensive activity study was performed for each compound. All compounds were tested for antibacterial activity. Moreover, in silico studies were carried out to determine the anticancer potential of the designed WZ1-WZ4 ligands. Based on molecular docking, aldehyde dehydrogenase was selected as a molecular target. The obtained data were compared with experimental data in vitro tests. Novel hybrids of the thiosemicarbazide scaffold and sulfonyl groups may have promising anticancer activity via the aldehyde dehydrogenase pathway. The best candidate for further studies appears to be WZ2, due to its superior selectivity in comparison to the other tested compounds.

2-(5,6-Diphenyl-1,2,4-triazin-3-yl)aniline.

The title compound, C21H16N4, obtained under standard Suzuki cross-coupling conditions, is a model compound in the synthesis and biological activity evaluation of new aza-analogues of sildenafil containing a pyrazolo-[4,3-e][1,2,4]triazine system. An N-H⋯N intra-molecular hydrogen bond involving the amino-benzene system and the 1,2,4-triazine moiety helps to establish a near coplanar orientation of the rings with a dihedral angle of 12.04 (4)°, which is believed to be necessary for the biological activity of sildenafil analogues. The 1,2,4-triazine ring is slightly distorted from planarity [r.m.s deviation = 0.0299 (11) Å] and forms dihedral angles of 58.60 (4) and 36.35 (3)° with the pendant phenyl rings. The crystal packing features bifurcated N-H⋯(N,N) hydrogen bonds linking screw-axis-related mol-ecules into chains parallel to the [010] direction and π-π inter-actions, with a centroid-centroid separation of 3.8722 (7) Šand a slippage of 1.412 (3) Å. The crystal studied was a nonmerohedral twin with a ratio of 0.707 (2):0293 (2).

Ethyl 2-(3-methyl-5-sulfanyl-idene-4,5-dihydro-1H-1,2,4-triazol-4-yl)acetate.

The title compound, C7H11N3O2S, exists in the 5-thioxo tautomeric form. The 1,2,4-triazoline ring is essentially planar, with a maximum deviation of 0.010 (2) Šfor the substituted N atom. The ethyl acetate substituent is almost planar, with a maximum deviation of 0.061 (4) Šfor the methyl-ene C atom of the eth-oxy group. The angle between the mean plane of this substituent and the mean plane of the 1,2,4-triazoline ring is 89.74 (8)°. In the crystal, mol-ecules are linked by a combination of N-H⋯S, C-H⋯N and C-H⋯O hydrogen bonds into chains parallel to [100].

2-(3-Chloro-5,6-diphenyl-2,5-dihydro-1,2,4-triazin-5-yl)-2-methyl-propane-nitrile.

The title compound, C(19)H(17)ClN(4), was obtained from the reaction of 3-chloro-5,6-diphenyl-1,2,4-triazine with isobutyronitrile in the presence of lithium diisopropyl-amide as an unexpected product of covalent addition of isobutyronitrile carbanion to the C-5 atom of the 1,2,4-triazine ring. The 2,5-dihydro-1,2,4-triazine ring is essentially planar (r.m.s. deviation = 0.0059 Å) and the 5- and 6-phenyl substituents are inclined to its mean plane with dihedral angles of 89.97 (4) and 55.52 (5)°, respectively. Intra-molecular C-H⋯N inter-actions occur. In the crystal, mol-ecules related by a c-glide plane are linked into zigzag chains along [001] by N-H⋯N hydrogen bonds.