Role of Plant Materials with Anti-inflammatory Effects in Phytotherapy of Osteoarthritis.

Osteoarthritis (OA) is a common chronic articular degenerative disease characterized by articular cartilage degradation, synovial inflammation/immunity, and subchondral bone lesions. Recently, increasing interest has been devoted to treating or preventing OA with herbal medicines. The mechanism of action of plant raw materials used in osteoarthrosis treatment is well documented. They are sought after because of the high frequency of inflammation of the knee joint among both elderly and young people engaged in sports in which their knee joints are often exposed to high-stress conditions. The purpose of this work was to present some most effective and safe plant medicines with proven mechanisms of action that can help to alleviate the growing social problem of osteoarthrosis caused in recent years. A review of the available literature based primarily on the latest editions of ESCOP and EMA monographs and the latest scientific papers has made it possible to select and propose medical management of osteoarthrosis by ranking plant medicines according to their effectiveness. Clinical studies of raw plant materials, such as Harpagophyti radix, Olibanum indicum, and Urticae foliumet herba have indicated that these drugs should be considered the first choice in osteoarthrosis treatment. The efficacy of Rosae pseudo-fructus, Salicis cortex, Filipendulae ulmariae flos et herba, Ribis nigri folium, and externally applied Capsici fructus and Symphyti radix, has also been proven by pharmacological studies. All the plant medicines mentioned in the paper have been studied in detail in terms of their phytochemistry, which can help doctors in their decision-- making in the treatment of osteoarthrosis.

Synthesis and Spectroscopic Characterization of Selected Water-Soluble Ligands Based on 1,10-Phenanthroline Core.

Water-soluble ligands based on a 1,10-phenanthroline core are relatively poorly studied compounds. Developing efficient and convenient syntheses of them would result in new interesting applications because of the importance of 1,10-phenanthrolines. In this manuscript, we describe novel and practical ways to introduce a carboxyl and, for the first time, a phenol and dithiocarboxyl group under mild reaction conditions. This strategy enables highly efficient and practical synthesis of suitable organosulfur compounds with high added value, high chemoselectivity, and a broad substrate range. We present the selective conversion of a hydroxydialdehyde in the form of 10-hydroxybenzo[h]quinoline-7,9-dicarbaldehyde into its derivative, unique hydroxydicarboxylic acid, by an oxidation procedure, giving 10-hydroxybenzo[h]quinoline-7,9-dicarboxylic acid. A similar procedure resulted in the formation of 9-methyl-1,10-phenanthroline-2-carboxylic acid by oxidation of commercially available neocuproine. An alternative method of obtaining 1,10-phenanthroline derivatives possessing carboxylic acid group can be based on the hydrolysis of ester or nitrile groups; however, this synthesis leads to unexpected products. Moreover, we apply Perkin condensation to synthesize a vinyl (or styryl) analog of 1,10-phenanthroline derivatives with phenol function. This reaction also demonstrates a new, simple, and efficient strategy for converting methyl derivatives of 1,10-phenanthroline. We anticipate that the new way of converting methyl will find wide application in chemical synthesis.

Metal-free highly chemo-selective bisphosphorylation and deoxyphosphorylation of carboxylic acids.

Carboxylic acids are readily available in both the natural and synthetic world. Their direct utilization for preparing organophosphorus compounds would greatly benefit the development of organophosphorus chemistry. In this manuscript, we describe a novel and practical phosphorylating reaction under transition metal-free reaction conditions that can selectively convert carboxylic acids into the P-C-O-P motif-containing compounds through bisphosphorylation, and the benzyl phosphorus compounds through deoxyphosphorylation. This strategy provides a new route for carboxylic acid conversion as the alkyl source, enabling highly efficient and practical synthesis of the corresponding value-added organophosphorus compounds with high chemo-selectivity and wide substrate scope, including the late modification of complex APIs (active pharmaceutical ingredients). Moreover, this reaction also indicates a new strategy for converting carboxylic acids into alkenes by coupling this work and the subsequent WHE reaction with ketones and aldehydes. We anticipate that this new mode of transforming carboxylic acids will find wide application in chemical synthesis.

Synthesis and Spectroscopic Characterization of Selected Phenothiazines and Phenazines Rationalized Based on DFT Calculation.

Two unique structures were isolated from the phosphorylation reaction of 10H-phenothiazine. The 5,5-dimethyl-2-(10H-phenothiazin-10-yl)-1,3,2-dioxaphosphinane 2-oxide (2a) illustrates the product of N-phosphorylation of phenothiazine. Moreover, a potential product of 2a instability, a thiophosphoric acid 2b, was successfully isolated and structurally characterized. Molecule 2a, similarly to sulfoxide derivative 3, possesses interesting phosphorescence properties due to the presence of d-pπ bonds. The X-ray, NMR, and DFT computational studies indicate that compound 2a exhibits an anomeric effect. Additionally, the syntheses of selected symmetrical and unsymmetrical pyridine-embedded phenazines were elaborated. To compare the influence of phosphorus and sulfur atoms on the structural characteristics of 10H-phenothiazine derivatives, the high-quality crystals of (4a,12a-dihydro-12H-benzo[5,6][1,4]thiazino[2,3-b]quinoxalin-12-yl)(phenyl)methanone (1) and selected phenazines 5,12-diisopropyl-3,10-dimethyldipyrido[3,2-a:3',2'-h]phenazine (5) and 5-isopropyl-N,N,3-trimethylpyrido[3,2-a]phenazin-10-amine (6a) were obtained. The structures of molecules 1, 2a, 2-mercapto-5,5-dimethyl-1,3,2-dioxaphosphinane 2-oxide (2b), 3,7-dinitro-10H-phenothiazine 5-oxide (3), 5 and 6a were determined by single-crystal X-ray diffraction measurements.

The Synthesis of Hypodiphosphoric Acid and Derivatives with P-P Bond, including Esters and Diphosphine Dioxides: A Review.

The synthesis of hypodiphosphoric acid and its related compounds began in 1877, but no summary of the synthetic efforts has been reported. This review includes published papers related to the molecules containing the >P(=O)-P(=O)< fragment, which notably resembles the structure of the >P(=O)-O-P(=O)< moiety, the essential building block of many important molecules found in nature and in the field of medicinal chemistry. This review covers the strategies related to the synthesis of hypodiphosphoric acid (former name hypophosphoric acid), its ester form, and diphosphine dioxides. Finally, some properties and applications of these structures studied during this period are presented.

Vanadium(IV) Complexes with Methyl-Substituted 8-Hydroxyquinolines: Catalytic Potential in the Oxidation of Hydrocarbons and Alcohols with Peroxides and Biological Activity.

Methyl-substituted 8-hydroxyquinolines (Hquin) were successfully used to synthetize five-coordinated oxovanadium(IV) complexes: [VO(2,6-(Me)2-quin)2] (1), [VO(2,5-(Me)2-quin)2] (2) and [VO(2-Me-quin)2] (3). Complexes 1-3 demonstrated high catalytic activity in the oxidation of hydrocarbons with H2O2 in acetonitrile at 50 °C, in the presence of 2-pyrazinecarboxylic acid (PCA) as a cocatalyst. The maximum yield of cyclohexane oxidation products attained was 48%, which is high in the case of the oxidation of saturated hydrocarbons. The reaction leads to the formation of a mixture of cyclohexyl hydroperoxide, cyclohexanol and cyclohexanone. When triphenylphosphine is added, cyclohexyl hydroperoxide is completely converted to cyclohexanol. Consideration of the regio- and bond-selectivity in the oxidation of n-heptane and methylcyclohexane, respectively, indicates that the oxidation proceeds with the participation of free hydroxyl radicals. The complexes show moderate activity in the oxidation of alcohols. Complexes 1 and 2 reduce the viability of colorectal (HCT116) and ovarian (A2780) carcinoma cell lines and of normal dermal fibroblasts without showing a specific selectivity for cancer cell lines. Complex 3 on the other hand, shows a higher cytotoxicity in a colorectal carcinoma cell line (HCT116), a lower cytotoxicity towards normal dermal fibroblasts and no effect in an ovarian carcinoma cell line (order of magnitude HCT116 > fibroblasts > A2780).

Direct Amination of Nitroquinoline Derivatives via Nucleophilic Displacement of Aromatic Hydrogen.

The vicarious nucleophilic substitution of hydrogen (VNS) reaction in electron-deficient nitroquinolines was studied. Properties of all new products have been characterized by several techniques: MS, HRMS, FTIR, GC-MS, electronic absorption spectroscopy, and multinuclear NMR. The structures of 4-chloro-8-nitroquinoline, 8-(tert-butyl)-2-methyl-5-nitroquinoline, 9-(8-nitroquinolin-7-yl)-9H-carbazole and (Z)-7-(9H-carbazol-9-yl)-8-(hydroxyimino)quinolin-5(8H)-one were determined by single-crystal X-ray diffraction measurements. The 9-(8-nitroquinolin-7-yl)-9H-carbazole and (Z)-7-(9H-carbazol-9-yl)-8-(hydroxyimino)quinolin-5(8H)-one illustrate the nitro/nitroso conversion within VNS reaction. Additionally, 9-(8-isopropyl-2-((8-isopropyl-2-methyl-5-nitroquinolin-6-yl)methyl)-5-nitrosoquinolin-6-yl)-9H-carbazole is presented as a double VNS product. It is postulated that the potassium counterion interacts with the oxygen on the nitro group, which could influence nucleophile attack in that way.

Synthesis, Electrochemical and Spectroscopic Characterization of Selected Quinolinecarbaldehydes and Their Schiff Base Derivatives.

A new approach to the synthesis of selected quinolinecarbaldehydes with carbonyl groups located at C5 and/or in C7 positions is presented in this paper in conjunction with spectroscopic characterization of the products. The classical Reimer-Tiemann, Vilsmeier-Haack and Duff aldehyde synthesis methods were compared due to their importance. Computational studies were carried out to explain the preferred selectivity of the presented formylation transformations. A carbene insertion reaction based on Reimer-Tiemann methodology is presented for making 7-bromo-8-hydroxyquinoline-5-carbaldehyde. Additionally, Duff and Vilsmeier-Haack reactions were used in the double formylation of quinoline derivatives and their analogues benzo[h]quinolin-10-ol, 8-hydroxy-2-methylquinoline-5,7-dicarbaldehyde, 8-(dimethylamino) quinoline-5,7-dicarbaldehyde and 10-hydroxybenzo[h]quinoline-7,9-dicarbaldehyde. Four Schiff base derivatives of 2,6-diisopropylbenzenamine were prepared from selected quinoline-5-carbaldehydes and quinoline-7-carbaldehyde by an efficient synthesis protocol. Their properties have been characterized by a combination of several techniques: MS, HRMS, GC-MS, FTIR, electronic absorption spectroscopy and multinuclear NMR. The electrochemical properties of 8-hydroxy-quinoline-5-carbaldehyde, 6-(dimethylamino)quinoline-5-carbaldehyde and its methylated derivative were investigated, and a strong correlation between the chemical structure and obtained reduction and oxidation potentials was found. The presence of a methyl group facilitates oxidation. In contrast, the reduction potential of methylated compounds was more negative comparing to non-methylated structure. Calculations of frontier molecular orbitals supported the finding. The structures of 8-hydroxy-2-methylquinoline-5,7-dicarbaldehyde and four Schiff bases were determined by single-crystal X-ray diffraction measurements.

Synthesis and Electrochemical and Spectroscopic Characterization of 4,7-diamino-1,10-phenanthrolines and Their Precursors.

New approaches to the synthesis of 4,7-dichloro-1,10-phenanthrolines and their corresponding 9H-carbazol-9-yl-, 10H-phenothiazin-10-yl- and pyrrolidin-1-yl derivatives were developed. Their properties have been characterized by a combination of several techniques: MS, HRMS, GC-MS, electronic absorption spectroscopy and multinuclear NMR in both solution and solid state including 15N CP/MAS NMR. The structures of 5-fluoro-2,9-dimethyl-4,7-di(pyrrolidin-1-yl)-1,10-phenanthroline (5d), 4,7-di(9H-carbazol-9-yl)-9-oxo-9,10-dihydro-1,10-phenanthroline-5-carbonitrile (6a) and 4,7-di(10H-phenothiazin-10-yl)-1,10-phenanthroline-5-carbonitrile (6b) were determined by single-crystal X-ray diffraction measurements. The nucleophilic substitutions of hydrogen followed by oxidation produced compounds 6a and 6b. The electrochemical properties of selected 1,10-phenanthrolines were investigated using cyclic voltammetry and compared with commercially available reference 1,10-phenanthrolin-5-amine (5l). The spatial distribution of frontier molecular orbitals of the selected compounds has been calculated by density functional theory (DFT). It was shown that potentials of reduction and oxidation were in consistence with the level of HOMO and LUMO energies.

Identification and derivatization of selected cathinones by spectroscopic studies.

In this study we identified three novel hydrochloride salts of cathinones 2-(pyrrolidin-1-yl)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)pentan-1-one (1a) (TH-PVP), 2-(methylamino)-1-(2-methylphenyl)-1-propanone (1b) (2-MMC) and 1-(4-chlorophenyl)-2-(methylamino)propan-1-one (1c) (4-CMC). Their properties have been examined through combinations of GC-MS, IR, NMR, electronic absorption spectroscopy and single crystal X-ray diffraction method. NMR solution spectra showed readily diagnostic H-1 and C-13 signals from methyl, N-methyl and carbonyl groups. Additionally the use of thionation and amination reactions for identification of selected cathinones was presented.

Electrochemistry and spectroelectrochemistry of bioactive hydroxyquinolines: a mechanistic study.

The oxidation mechanism of selected hydroxyquinoline carboxylic acids such as 8-hydroxyquinoline-7-carboxylic acid (1), the two positional isomers 2-methyl-8-hydroxyquinoline-7-carboxylic acid (3) and 2-methyl-5-hydroxyquinoline-6-carboxylic acid (4), as well as other hydroxyquinolines were studied in aprotic environment using cyclic voltammetry, controlled potential electrolysis, in situ UV-vis and IR spectroelectrochemistry, and HPLC-MS/MS techniques. IR spectroelectrochemistry showed that oxidation unexpectedly proceeds together with protonation of the starting compound. We proved that the nitrogen atom in the heterocycle of hydroxyquinolines is protonated during the apparent 0.7 electron oxidation process. This was rationalized by the autodeprotonation reaction by another two starting molecules of hydroxyquinoline, so that the overall oxidation mechanism involves two electrons and three starting molecules. Both the electrochemical and spectroelectrochemical results showed that the oxidation mechanism is not influenced by the presence of the carboxylic group in the chemical structure of hydroxyquinolines, as results from oxidation of 2,7-dimethyl-5-hydroxyquinoline (6). In the presence of a strong proton acceptor such as pyridine, the oxidation ECEC process involves two electrons and two protons per one molecule of the hydroxyquinoline derivative. The electron transfer efficiency of hydroxyquinolines in biosystems may be related to protonation of biocompounds containing nitrogen bases. Molecular orbital calculations support the experimental findings.

Synthesis, spectroscopy and computational studies of selected hydroxyquinolines and their analogues.

Synthetic, spectroscopy and mechanistic aspects of preparation of selected hydroxyquinolines and their analogues or derivatives contained methoxy, fluoro, chloro, carboxylic, carbodithioic and phosphinate or dioxaphosphinane groups were elaborated. The multinuclear NMR and five single crystal X-ray characteristics of the series of quinolines have been determined. The molecular orbitals of the selected hydroxyquinolines have been calculated by density functional theory. The X-ray and NMR studies of 8-[(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)oxy]-5,7-dibromo-2-methylquinoline and 8-[(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)oxy]-5-fluoro-2-methylquinoline indicate the appearance of anomeric effect.

Contribution to investigation of antimicrobial activity of styrylquinolines.

Series of new ring-substituted styrylquinolines and two oxorhenium complexes were prepared and characterized. The compounds were analyzed using RP-HPLC to determine lipophilicity. Primary in vitro screening of the synthesized compounds was performed against fungal and bacterial strains. Some compounds were active against bacteria at micromolar level and against fungi at submicromolar level. Compounds 5,7-dichloro-2-[2-(2-ethoxyphenyl)vinyl]quinolin-8-ol expressed excellent antifungal activity comparable with or higher than the standard fluconazole as well as antibacterial activity against Staphylococcus strains comparable with or higher than the standards bacitracin, penicillin and ciprofloxacin. The structure-activity relationships are discussed.

Investigating the activity spectrum for ring-substituted 8-hydroxyquinolines.

In this study, a series of fourteen ring-substituted 8-hydroxyquinoline derivatives were prepared. The synthesis procedures are presented. The compounds were analyzed using RP-HPLC to determine lipophilicity. They were tested for their activity related to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. Primary in vitro screening of the synthesized compounds was also performed against four mycobacterial strains and against eight fungal strains. Several compounds showed biological activity comparable with or higher than the standards isoniazid or fluconazole. For all the compounds, the relationships between the lipophilicity and the chemical structure of the studied compounds are discussed.

3-[(E)-2-(5,7-Dichloro-8-hydroxy-quinolin-2-yl)vin-yl]-4-hydroxy-phenyl acetate.

The two symmetry independent mol-ecules of the title compound, C(19)H(13)Cl(2)NO(4), show similar conformations with the acetyl group twisted strongly relative to the remaining, virtually flat (r.m.s. deviations = 0.0173 and 0.0065 Å), part of the mol-ecule. The hydroxyl groups of the 8-hydroxy-quinoline residues are involved in intra-molecular O-H⋯N hydrogen bonds, which, in one case, forms a part of a three-center inter-action. Inter-molecular O-H⋯O hydrogen bonds assemble the mol-ecules into a one-dimensional polymeric structure extended along the a axis. The 4-hydroxy-phenyl group of one mol-ecule forms an O-H⋯O hydrogen bond, in which the hydroxyl H atom is disordered, with its inversion center counterpart.

A solid state and solution NMR study of the tautomerism in hydroxyquinoline carboxylic acids.

Some hydroxyquinoline carboxylic acids and their conjugate acids and bases were characterized by 13C and 15N NMR spectroscopy in solution and in the solid state. Differences in 13C and, in particular, 15N chemical shift patterns allow to distinguish between individual tautomers and confirm the presence of zwitterionic species in the solid state. Solution NMR spectra in dimethyl sulfoxide (DMSO) show effects resulting as a consequence of dynamic exchange and suggest the presence of an equilibrium mixture of hydroxyquinoline carboxylic acid and zwitterionic hydroxyquinolinium carboxylate tautomers.

Synthesis and P-P cleavage reactions of [P(X)X']2; X-ray structures of [Co[P(X)X'](CO)3] and P4[P(X)X']2[X = N(SiMe3)2, X'= NPri2].

Treatment of P(X)(X')Cl with KC8 gave the crystalline diphosphine [P(X)X']2 (1) which dissociated reversibly into the phosphinyl radical *P(X)X' (2), a plausible intermediate in the reaction of with [Cr(CO)6], [Co(NO)(CO)3] or P4, yielding [Cr[P(X)X']2(CO)3] (3), [Co[P(X)X'](CO)3] (4), or 1,4-P4[P(X)X']2 (5); the P(X)X' substituent is pyramidal at P in but planar in [X = N(SiMe3)2, X'= NPri2].

Structures of the radical P[N(SiMe3)2](NPri2), its dimer, cation and chloro derivative.

Treatment of PCl[N(SiMe3)2](NPri2) (1) with potassium-graphite in thf afforded the colourless, crystalline diphosphine [P[N(SiMe3)2](NPri2)]2 (2) in good yield. Sublimation of 2 in vacuo yielded the yellow phosphinyl radical P[N(SiMe3)2](NPri2) (3), which upon cooling reverted to 2; the latter in C6D6 at 298 K was a mixture of rac and meso diastereoisomers. The yellow, crystalline phosphenium salt [P[N(SiMe3)2](NPri2)][AlCl4] (4) was obtained from 1 and 1/2Al2Cl6 in CH2Cl2. By single-crystal X-ray diffraction (XRD) the structures of the known compound 1 and of 2 and 4 were determined. The structure of the radical 3, formed by the thermal homolytic dissociation of the diphosphine 2, was determined in the gas phase by electron diffraction (GED), utilising data from UMP2/6-31+G*ab initio calculations. The model of the molecule in the GED structure analysis was described by a set of internal coordinates and an initial set of Cartesian coordinates from ab initio calculations, facilitating the structure analysis. The experimental data were found to be consistent with the presence of a single conformer of the radical in the gas phase. The computed standard homolytic dissociation enthalpy of the P-P bond in the corresponding diphosphine 2, corrected for BSSE, 54 kJ mol(-1), is substantially reduced compared to the dissociation enthalpy of tetramethyldiphosphine by the reorganisation energies of the fragments that form upon dissociation. The intrinsic energy content of the P-P bond in the diphosphine 2 was estimated to be 286 kJ mol(-1), in agreement with the results of previous work on a series of crowded diphosphines.

Synthesis, structure and reductive dechlorination of the C-centred phosphorus(III) beta-diketiminate PCl(Ph)L [L = C[C(Me)NC6H3Pri2(-2),6][C(Me)NHC6H3Pri2(-2),6]].

Treatment of the beta-diketimine HL with successively LiBun and PCl2Ph gave the first C-centered monodentate beta-diketiminate PCl(Ph)L 1; with C8K 1 underwent reductive dechlorination yielding 2, a novel N-PIII-PIII-C=C heterocycle.