Synthesis and Pharmacological Evaluation of (+)-Usnic Acid Derivatives as Hypoglycemic Agents

Usnic acid is produced by lichens and exhibits different biological properties, including hypoglycemic ones. However, this effect becomes noticeable only at relatively high doses, something that may lead to some adverse effects. The chemical modification of the molecule is able to enhance its safety profile and its hypoglycemic properties. We synthesized six enamine derivatives of (+)-usnic acid, and two of them are novel. All compounds were evaluated for the hypoglycemic effect after oral introduction in mice with alloxan-induced diabetes mellitus at a dose of 50 mg/kg. The derivative containing a 4-trifluoromethylphenyl fragment showed the most pronounced hypoglycemic effect, which was detected starting from sixth day of the experiment. Also, OGTT was performed in mice without alteration of glucose metabolism (C57BL/6), which showed no hypoglycemic effect after oral introduction of all studied compounds

Synthesis and Pharmacological Evaluation of (+)-Usnic Acid Derivatives as Hypoglycemic Agents

Usnic acid is produced by lichens and exhibits different biological properties, including hypoglycemic ones. However, this effect becomes noticeable only at relatively high doses, something that may lead to some adverse effects. The chemical modification of the molecule is able to enhance its safety profile and its hypoglycemic properties. We synthesized six enamine derivatives of (+)-usnic acid, and two of them are novel. All compounds were evaluated for the hypoglycemic effect after oral introduction in mice with alloxan-induced diabetes mellitus at a dose of 50 mg/kg. The derivative containing a 4-trifluoromethylphenyl fragment showed the most pronounced hypoglycemic effect, which was detected starting from sixth day of the experiment. Also, OGTT was performed in mice without alteration of glucose metabolism (C57BL/6), which showed no hypoglycemic effect after oral introduction of all studied compounds

Effect of Complexation with Arabinogalactan on Pharmacokinetics of “Guest” Drugs in Rats: For Example, Warfarin

A pharmacokinetic study of the warfarin (WF) : arabinogalactan (AG) complex with the 1 : 10 mass ratio after its intragastric introduction to Wistar rats at a dose of 5 mg/kg (WF dose in the complex was 0.5 mg/kg) once a day for three days was conducted. It was found that Cmax, T1/2, and AUC of WF in the complex form were lower than after the introduction of blank WF at the same dose, but its elimination (Cl, MRT) was much faster. Significant accumulation (Cmin) and an abrupt increase in plasma concentration after the third introduction were observed for blank WF, whereas the complex showed a much more moderate increase in concentration at this point. However, despite obvious differences in pharmacokinetic parameters, the efficacies of both agents were virtually identical; the complex differed from blank WF by only 15%. This value is rather insignificant and does not impair its anticoagulant activity. Thus, we can conclude that introduction of the WF : AG complex is safe in terms of reduction of the bleeding risk and accumulation

(1<i>R</i>,2<i>R</i>,4<i>R</i>)-<i>N</i>-((4-((4-(2-Carboxyethyl)phenoxy)methyl)thiophen-2-yl)methyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-aminium Chloride

A novel free fatty acid receptor 1 (FFAR1) agonist has been synthesized and evaluated in vitro. The synthesis of the title compound was performed from commercially available 4-hydroxybenzaldehyde, 2-thiophenecarboxaldehyde, and (+)-camphor. The compound was shown to have an affinity to FFAR1

Preparation of curcumin self-micelle solid dispersion with enhanced bioavailability and cytotoxic activity by mechanochemistry

An amorphous solid dispersion (SD) of curcumin (Cur) with disodium glycyrrhizin (Na2GA) was prepared by mechanical ball milling. Curcumin loaded micelles were self-formed by Na2GA when SD dissolved in water. The physical properties of Cur SD in solid state were characterized by differential scanning calorimetry, X-ray diffraction studies, and scanning electron microscope. The characteristics of the sample solutions were analyzed by reverse phase HPLC, UV–visible spectroscopy, 1H NMR spectroscopy, gel permeation LC, and transmission electron microscopy. In vitro cytotoxic tests demonstrated that Cur SD induced higher cytotoxicity against glioblastoma U-87 MG cells than free Cur. Besides, an improvement of membrane permeability of Cur SD was confirmed by parallel artificial membrane permeability assay. Further pharmacokinetic study of this SD formulation in rat showed a significant ∼19-fold increase of bioavailability as comparing to free Cur. Thus, Cur SD provide a more potent and efficacious formulation for Cur oral delivery

Hydroxyapatite Double Substituted with Zinc and Silicate Ions: Possibility of Mechanochemical Synthesis and In Vitro Properties

In this study, the mechanochemical synthesis of substituted hydroxyapatite (HA) containing zinc and silicon ions having a chemical formula of Ca10−xZnx(PO4)6−x(SiO4)x(OH)2−x, where x = 0.2, 0.6, 1.0, 1.5, and 2.0, was carried out. The synthesized materials were characterized by powder X-ray diffraction, Fourier transform infrared spectroscopy, transmission electron microscopy, and inductively coupled plasma spectroscopy. We found that HA co-substituted with zinc and silicate formed up to x = 1.0. At higher concentrations of the substituents, the formation of large amounts of an amorphous phase was observed. The cytotoxicity and biocompatibility of the co-substituted HA was studied in vitro on Hek293 and MG-63 cell lines. The HA co-substituted with zinc and silicate demonstrated high biocompatibility; the lowest cytotoxicity was observed at x = 0.2. For this composition, good proliferation of MG-63 osteoblast-like cells and an increased solubility compared with that of HA were detected. These properties allow us to recommend the synthesized material for medical applications, namely, for the restoration of bone tissue and manufacture of biodegradable implants

Hydroxyapatite Double Substituted with Zinc and Silicate Ions: Possibility of Mechanochemical Synthesis and In Vitro Properties

In this study, the mechanochemical synthesis of substituted hydroxyapatite (HA) containing zinc and silicon ions having a chemical formula of Ca10&minus;xZnx(PO4)6&minus;x(SiO4)x(OH)2&minus;x, where x = 0.2, 0.6, 1.0, 1.5, and 2.0, was carried out. The synthesized materials were characterized by powder X-ray diffraction, Fourier transform infrared spectroscopy, transmission electron microscopy, and inductively coupled plasma spectroscopy. We found that HA co-substituted with zinc and silicate formed up to x = 1.0. At higher concentrations of the substituents, the formation of large amounts of an amorphous phase was observed. The cytotoxicity and biocompatibility of the co-substituted HA was studied in vitro on Hek293 and MG-63 cell lines. The HA co-substituted with zinc and silicate demonstrated high biocompatibility; the lowest cytotoxicity was observed at x = 0.2. For this composition, good proliferation of MG-63 osteoblast-like cells and an increased solubility compared with that of HA were detected. These properties allow us to recommend the synthesized material for medical applications, namely, for the restoration of bone tissue and manufacture of biodegradable implants

Synthesis and Evaluation of Hypoglycemic Activity of Structural Isomers of ((Benzyloxy)phenyl)propanoic Acid Bearing an Aminobornyl Moiety

Free fatty acid receptor-1 (FFAR1) agonists are promising candidates for therapy of type 2 diabetes because of their ability to normalize blood sugar levels during hyperglycemia without the risk of hypoglycemia. Previously, we synthesized compound QS-528, a FFA1 receptor agonist with a hypoglycemic effect in C57BL/6NCrl mice. In the present work, structural analogs of QS-528 based on (hydroxyphenyl)propanoic acid bearing a bornyl fragment in its structure were synthesized. The seven novel compounds synthesized were structural isomers of compound QS-528, varying the positions of the substituents in the aromatic fragments as well as the configuration of the asymmetric center in the bornyl moiety. The studied compounds were shown to have the ability to activate FFAR1 at a concentration of 10 μM. The cytotoxicity of the compounds as well as their effect on glucose uptake in HepG2 cells were studied. The synthesized compounds were found to increase glucose uptake by cells and have no cytotoxic effect. Two compounds, based on the meta-substituted phenylpropanoic acid, 3-(3-(4-(((1R,2R,4R)-1,7,7-trimethylbicyclo-[2.2.1]heptan-2-ylamino)methyl)benzyloxy)phenyl)propanoic acid and 3-(3-(3-(((1R,2R,4R)-1,7,7-trimethylbicyclo [2.2.1]heptan-2-ylamino)methyl)benzyloxy)phenyl)propanoic acid, were shown to have a pronounced hypoglycemic effect in the oral glucose tolerance test with CD-1 mice

Solubility, Permeability, Anti-Inflammatory Action and In Vivo Pharmacokinetic Properties of Several Mechanochemically Obtained Pharmaceutical Solid Dispersions of Nimesulide

Nimesulide (NIM, N-(4-nitro-2-phenoxyphenyl)methanesulfonamide) is a relatively new nonsteroidal anti-inflammatory analgesic drug. It is practically insoluble in water (&lt;0.02 mg/mL). This very poor aqueous solubility of the drug may lead to low bioavailability. The objective of the present study was to investigate the possibility of improving the solubility and the bioavailability of NIM via complexation with polysaccharide arabinogalactan (AG), disodium salt of glycyrrhizic acid (Na2GA), hydroxypropyl-β-cyclodextrin (HP-β-CD) and MgCO3. Solid dispersions (SD) have been prepared using a mechanochemical technique. The physical properties of nimesulide SD in solid state were characterized by differential scanning calorimetry and X-ray diffraction studies. The characteristics of the water solutions which form from the obtained solid dispersions were analyzed by reverse phase and gel permeation HPLC. It was shown that solubility increases for all complexes under investigation. These phenomena are obliged by complexation with auxiliary substances, which was shown by 1H-NMR relaxation methods. The parallel artificial membrane permeability assay (PAMPA) was used for predicting passive intestinal absorption. Results showed that mechanochemically obtained complexes with polysaccharide AG, Na2GA, and HP-β-CD enhanced permeation of NIM across an artificial membrane compared to that of the pure NIM. The complexes were examined for anti-inflammatory activity on a model of histamine edema. The substances were administered per os to CD-1 mice. As a result, it was found that all investigated complexes dose-dependently reduce the degree of inflammation. The best results were obtained for the complexes of NIM with Na2GA and HP-β-CD. In noted case the inflammation can be diminished up to 2-fold at equal doses of NIM

Discovery of the First in Class 9-N-Berberine Derivative as Hypoglycemic Agent with Extra-Strong Action

Berberine is well known for its ability to reduce the blood glucose level, but its high effective dose and poor bioavailability limits its use. In this work we synthesized a new derivative of berberine, 9-(hexylamino)-2,3-methylenedioxy-10-methoxyprotoberberine chloride (SHE-196), and analyzed the profile of its hypoglycemic effects. Biological tests have shown that the substance has a very pronounced hypoglycemic activity due to increased insulin sensitivity after single and multiple dosing. In obese type 2 diabetes mellitus (T2DM) mice, it was characterized by improved glucose tolerance, decreased fasting insulin levels and sensitivity, decreased total body weight and interscapular fat mass, and increased interscapular brown fat activity. All these effects were also confirmed histologically, where a decrease in fatty degeneration of the liver, an improvement in the condition of the islets of Langerhans and a decrease in the size of fat droplets in brown adipose tissue were found. Our results indicate that 9-(hexylamino)-2,3-methylenedioxy-10-methoxyprotoberberine chloride could be the first in a new series of therapeutic agents for the treatment of diabetes mellitus