New A-seco-derivatives of methyl glycyrrhetinate (MeGLC) were synthesized. Cleavage of ring A of the 2-hydroxymethylene-3-oxo-derivative of MeGLC by H2O2 (30

The review summarizes current literature data on the mechanism of antithrombotic, anti-inflammatory, and antipyretic effects of acetylsalicylic acid (ASA), which is widely used in medicine. The use of ASA may be accompanied by several complications from the gastrointestinal tract (ulcers and bleeding), nephrotoxicity, the development of bronchospasm (aspirin triad), and clinical manifestations of aspirin resistance. The advantages and shortcomings of the main methods of preventing undesirable side effects when taking low doses of ASA are considered: the use of proton-pump inhibitors and rebamipide and inclusion of ASA complexes as promising dosage forms. The pharmacological properties of glycyrrhizic acid (GA) and its ability for clathrate formation with known drugs, in particular ASA, are considered. The advantages of a dosage form of GA with ASA with the same or improved pharmacological activity and reduced toxic side effects of the latter are shown. The review presents data for the last 10 – 11 years gained through the Russian and international search systems PubMed, eLibrary, etc.

C30-amides of 3-O-acetylglycyrrhetic acid containing aromatic and heterocyclic pharmacophores were synthesized by the acid chloride method. The antiulcer activity of 3-O-acetylglycyrrhetic acid amides with piperazine (IV), aniline (VI), and 2-aminothiazole-3-phenyl (X) was studied in the indomethacin ulcer model of the gastric mucosa of rats at a dose of 50 mg/kg. Amides IV and X had the highest antiulcer activity comparable to that of the reference drug Omez.

The synthesis of 2,3-indoles of Glycyrrhetinic acid (GLA) and its methyl ester was carried out by the Fischer reaction. Reductive transformations of GLA methyl ester 2,3-indole 3a were carried out to obtain 11-deoxo- and 9,12-diene analogs. N-methylation of 2,3-indole 3a gave N-methyl-indole-11-oxo-18β-olean-12-en-30-oic acid. The antiulcer and anti-inflammatory activity of 2,3-indole 3a was studied in rats and mice. It was found, compound 3a exhibied a pronounced antiulcer activity in the indomethacin model of ulcers in rats and anti-inflammatory activity in the carrageenan model of acute edoema in mice, at a dose of 50 mg/kg. This is the first report of anti-ulcer and anti-inflammatory activities of 2,3-indolo-GLA derivatives.

The cytotoxic activity of a number of A-modified derivatives of glycyrrhetic acid (GLA) and 11-deoxo- and 18,19-dehydro-GLA against conditionally normal HEK 293 cells, A549 human lung carcinoma, MCF-7 breast adenocarcinoma, and SH-SY5Y neuroblastoma cells was studied. The most active compound was 18,19-dehydro-GLA methyl ester with a pyrazole fragment, which exhibited a pronounced cytotoxic effect against A549, MCF-7, and SH-SY5Y cancer cell lines (IC 50 22.57 – 38.11 μM).

3-Hydroxyimino derivatives of minor licorice triterpenoids possessed pronounced antiulcer activity and protected rat gastric mucosa from ulceration in indomethacin and orthophen ulcer models at a dose of 50 mg/kg. 3-Hydroxyimino-11-deoxoglycyrrhetic acid was the most active antiulcerogenic substance and was superior in activity to carbenoxolone.

3-Оксиимино-производные минорных тритерпеноидов солодки обладают выраженной противоязвенной активностью и предохраняют слизистую оболочку желудка крыс от изъязвления на модели индометациновых и ортофеновых язв в дозе 50 мг/кг. 3-Окси-имин 11-дезоксо-глицирретовой кислоты является наиболее активным антиульцерогенным веществом, превосходящим по активности карбеноксолон.

A 1:4 inclusion complex of 11-deoxymisoprostol (II) with glycyrrhizic acid (complex III) was synthesized and exhibited high anti-ulcer activity in experimental models of gastric mucosal ulcers (GMUs) inWistar rats induced by indomethacin and diclofenac. Complex III at a dose of 1 mg/kg (0.1 mg of II) reduced the number of indomethacin gastric ulcers by 46.4% (p < 0.012) as compared with the control group and by 39.2% as compared with II at the same dose. The anti-ulcer activity of complex III at a dose of 1 mg/kg was 5.8 times higher than that of the initial prostaglandin at an equivalent dose (0.1 mg/kg) in a model of gastric ulcers caused by diclofenac.

Conjugates of glycyrrhizic acid (GA) with methyl esters of L-amino acids (valine, methionine, and glutamic acid) containing the amino-acid residues in the carbohydrate moiety of the glycoside were synthesized using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The resulting GA conjugates at a dose of 2 mg/kg stimulated a primary immune response (production of antibody-forming cells, AFCs) in outbred mice by 1.6 - 3 times as compared with the control. The conjugate of GA with Glu(OMe)2 stimulated antibody genesis in outbred mice 1.7 times more efficiently than N-acetylmuramyl dipeptide and showed a stimulating effect on AFC production in the spleen of CBA mice.

Claisen–Schmidt reactions of 3-oxoglycyrrhetic acid with aromatic aldehydes in EtOH–NaOH (4N) synthesized 2-arylidene-3-oxo-derivatives in 65–70% yields. The structures of the compounds were confirmed by PMR and 13 C NMR spectra using 2D correlation methods.

The hypoglycemic activity of glycyrrhizic acid (GA, I), its trisodium (II) and sodium-dilithium salts (III), and a conjugate with L-methionine methyl ester (IV) was studied using an alloxan diabetes model after peroral administration to male Wistar rats. It was found that GA and its conjugate IV at a dose of 100 mg/kg exhibited hypoglycemic activity and reduced the blood glucose content of the animals by 35.5 and 42.6%, respectively, after 120 min. GA conjugate IV had low toxicity and hypoglycemic activity superior to those of GA and acarbose.

Изучена гипогликемическая активность глицирризиновой кислоты (ГК) (I) и ее производных — тринатриевой (II), натрий-дилитиевой (III) солей и конъюгата с метиловым эфиром L-метионина (IV) при пероральном введении крысам-самцам линии Вистар на модели аллоксанового диабета. Установлено, что ГК и ее конъюгат IV в дозе 100 мг/кг обладают гипогликемической активностью и снижают содержание глюкозы в крови животных на 35,5 и 42,6 %, соответственно, через 120 мин. Конъюгат ГК (IV) является малотоксичным веществом и превосходит по гипогликемической активности ГК и акарбозу.

A new method for the synthesis of glycyrrhizic acid (GA) conjugates with S-benzyl-L-cysteine using 1-ethyl-3-(3-dimethylaminoproopyl)carbodiimide is proposed. It is established that 3-O-{2-O-[N-(β-D-glucopyranosyluronyl)-L-cysteine-S-benzyl]-N-(β-D-glucopyranosyluronyl)-L-cysteine-S-benzyl}-(3β,20β)-11-oxo-30-(N-carbonyl-L-cysteine-S-benzyl)-30-norolean-12-ene is superior to GA in inhibiting the accumulation of HIV-I virus-specific protein p24 (viral antigen) in MT-4 cell culture (IC50 3 μg/mL, SI 90) and is 50 – 55 times less toxic to cells than azidothymidine.

Предложен новый способ синтеза конъюгатов глицирризиновой кислоты (ГК) с S-бензил-L-цистеином с использованием 1-этил-3-(3-диметиламинопропил)карбодиимида. Установлено, что 3-О-{2-О-[N-(β-D-глюкопиранозилуроноил)-L-цистеин-S-бензил]-N-(β-D-глюкопиранозилуроноил)-L-цистеин-S-бензил}-(3β,20β)-11-оксо-30-(N-карбонил-L- цистеин-S-бензил)-30-норолеан-12-ен превосходит ГК по ингибированию накопления вирусоспецифического белка р24 (вирусного антигена) ВИЧ-1 в культуре клеток МТ-4 (IC50 3 мкг/мл, SI 90) и является в 50 – 55 раз менее токсичным веществом для клеток, чем азидотимидин.

The search for new drugs to treat viral infections and immune deficiencies of various etiologies is still one of the most important tasks of medicinal chemistry, pharmacy, and medicine due to the widespread prevalence of a number of socially dangerous viral infections. This review focuses on the chemical modification of Glycyrrhizic acid (Gl), the main component of licorice root, which is currently a leading natural glycoside that is considered to be promising for the development of new antiviral agents. The review presents the results of studies conducted over the past 15 years to obtain a library of Gl acid derivatives for biological studies and to search for leader compounds. The synthesis of new biologically active derivatives and analogues (conjugates with amino acids and dipeptides, amino sugars, licorice triterpene acids conjugates with amino sugars, saponins and mono glycosides, and heterocyclic amides) was conducted, and their antiviral and immune modulating properties were studied. Potent inhibitors of HIV, SARS CoV, Epstein-Barr, and influenza A/H1N1 viruses and the stimulators of primary immune response were found among the Gl derivatives and analogues that were produced.

The tetra-O-methyl ether of quercetin (QU) 3 (54%), 3,7,4′-tri-O-methyl ether 4 (30%), and a previously unreported 3,7,3-tri-O-methyl ether of QU 5 (7%) were obtained via methylation of QU by an excess of diazomethane in dioxane. Their structures were established using 2D NMR (1H–1H COSY, 1H–1H NOESY, 1H–13C HSQC, 1H–13C HMBC). Tetra-O-methyl ether of QU 3 exhibited pronounced hypoglycemic activity, reduced alloxan-induced hyperglycemia in rats by 44.5% compared to a control, and was 2.7 times more active than QU.

New derivatives of glycyrrhetic acid with hydrazide pharmacophore groups were synthesized and their antimicrobial activity was evaluated. Hydrazide of 3- O -acetyl- N '-(4-hydroxybenzylidene) glycyrrhetic acid exhibited the highest antimicrobial activity. This compound had both an antibacterial effect against Escherichia coli , Proteus vulgaris , Klebsiella pneumonia , Staphylococcus aureus , Citrobacter diversus , Enterobacter aerogenes , Pseudomonas aeruginosa , and Enterobacter cloacae and antifungal activity against the Candida albicans fungus. The minimum inhibitory concentrations of this compound and pimafucin were similar for Candida albicans .