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Dengue virus (DENV) is one of the most geographically distributed mosquito-borne flaviviruses, like Japanese encephalitis virus (JEV), and Zika virus (ZIKV). In this study, a library of the known and novel Glycyrrhizic acid (GL) derivatives bearing amino acid residues or their methyl/ethyl esters in the carbohydrate part were synthesized and studied as DENV inhibitors in vitro using the cytopathic effect (CPE), viral infectivity and virus yield assays with DENV1 and DENV-2 in Vero E6 and A549 cells. Among the GL conjugates tested, compound hits GL-D-ValOMe 3, GL-TyrOMe 6, GL-PheOEt 11, and GL-LysOMe 21 were discovered to have better antiviral activity than GL, with IC50 values ranging from

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.

Paeoniflorin per-O-benzoates with the preserved pinane structure 2 and rearranged aglycone 3, containing C4 = O function, were obtained and their influence on learning and memory of aged rats was studied in the passive avoidance task. It was found that the chemical modification of paeoniflorin affected the cognitive functions of aged rats. The introduction of C4 = O function into the pinane part of benzoate 3 led to the improvement in learning process and preservation of the memory trace in aged rats as compared to the natural glycoside. This compound can be considered as the promising for further studies on in vivo models of disorders characteristic for Alzheimer's disease.

Graphical abstract, Highlights • It is the first report to display structure-anti-DENV activity relationships of Glycyrrhizic acid (GL) derivatives. • GL conjugates with isoleucine 13 and 11-aminoundecanoic acid 17 have been identified as potent DENV2 inhibitors. • GL derivatives 13 and 17 showed lower IC50 values (1.2–1.3 μM) against DENV2 infectivity in Vero E6 cells than GL (IC50 8.1 μM)., Dengue virus (DENV) is one of the most geographically distributed pathogenic flaviviruses transmitted by mosquitoes Aedes sps. In this study, the structure-antiviral activity relationships of Glycyrrhizic acid (GL) derivatives was evaluated by the inhibitory assays on the cytopathic effect (CPE) and viral infectivity of DENV type 2 (DENV2) in Vero E6 cells. GL (96% purity) had a low cytotoxicity to Vero E6 cells, inhibited DENV2-induced CPE, and reduced the DENV-2 infectivity with the IC50 of 8.1 μM. Conjugation of GL with amino acids or their methyl esters and the introduction of aromatic acylhydrazide residues into the carbohydrate part strongly influenced on the antiviral activity. Among compounds tested GL conjugates with isoleucine 13 and 11-aminoundecanoic acid 17 were found as potent anti-DENV2 inhibitors (IC50 1.2–1.3 μM). Therefore, modification of GL is a perspective way in the search of new antivirals against DENV2 infection.

Zika virus (ZIKV) is a new pathogenic flavivirus transmitted by mosquitoes Aedes spp. ZIKV infection is accompanied by serious neurological complications and is especially dangerous for pregnant women, in which it can lead to congenital malformations of the fetus and microcephaly in neonates. Currently, there are no licensed vaccines or specific post-infectious therapies for ZIKV infection. This report is devoted to the study of glycyrrhizic acid (GL) derivatives as ZIKV inhibitors. The inhibitory assays on the cytopathic effect (CPE) and viral infectivity of ZIKV in three different human cell lines revealed that the conjugation of GL with amino acids and their esters (methyl, ethyl) is influenced by the antiviral activity of the compounds. GL conjugates with Glu(OMe)-OMe 11, Glu(OH)-OMe 12, Asp(OMe)-OMe 13, TyrOMe 14, LeuOEt 15, and PheOEt 16 with free COOH groups in the triterpene moiety were active against ZIKV. The most active compounds 13 and 14 have IC50 values of 0.23 μM and 0.09 μM against low doses (MOI = 0.05) of ZIKV strain PRVABC59, 1.20 μM and 0.74 μM against high doses (MOI = 10) of ZIKV strain Natal RGN single-round infectious particles, respectively. The lead compound was 14 with a high selectivity index (SI < 500). Compound 13 showed a higher inhibitory effect on the early stage (entry) of ZIKV replication than compound 14, and was less potent than compound 14 at the post-entry stage, consistent with the docking models. Compounds 13 and 14 also had a strong interaction with the active site pocket of NS5 MTase. Compounds 13 and 14 are recommended for expanded antiviral studies against ZIKV infection.

Glycyrrhizic acid (18beta-GL or GL) is a herbal drug with a broad spectrum of antiviral activities and pharmacological effects and multiple sites of action. Previously we showed that GL inhibits Epstein-Barr virus (EBV) infection in vitro by interfering with an early step of the EBV replication cycle (possibly attachment/penetration). Here we tested the effects of 15 GL derivatives against EBV infection by scoring the numbers of cell expressing viral antigens and quantifying EBV DNA copy numbers in superinfected Raji cells. The derivatives were made either by transformation of GL on carboxyl and hydroxyl groups or by conjugation of amino acid residues into the carbohydrate part. We identified seven compounds active against EBV and all showed dose-dependent inhibition as determined by both assays. Among these active compounds, the introduction of amino acid residues into the GL carbohydrate part enhanced the antiviral activity in three of the seven active compounds. However, when Glu(OH)-OMe was substituted by Glu(OMe)-OMe, its antiviral activity was completely abolished. Introduction of potassium or ammonium salt to GL reduced the antiviral activity with no significant effect on cytotoxicity. The alpha-isomer (18alpha-GL) of 18beta-GL was as potent as the beta-form, but its sodium salt lost antiviral activity. The metabolic product of GL, 18beta-glycyrrhetinic acid (18beta-GA or GA), was 7.5-fold more active against EBV than its parental compound GL but, concomitantly, exhibited increased cytotoxicity resulting in a decreased therapeutic index.

Glycyrrhizin (GL) was shown to inhibit SARS-coronavirus (SARS-CoV) replication in vitro. Here the anti-SARS-CoV activity of 15 GL derivatives was tested. The introduction of 2-acetamido-beta-d-glucopyranosylamine into the glycoside chain of GL resulted in 10-fold increased anti-SARS-CoV activity compared to GL. Amides of GL and conjugates of GL with two amino acid residues and a free 30-COOH function presented up to 70-fold increased activity against SARS-CoV but also increased cytotoxicity resulting in decreased selectivity index.

Reaction of quercetin (QR) (1) with bromine under various conditions was studied. Interaction of QR with 2–3 equiv. of bromine in glacial acetic acid at 35–40°C for 2–4 h and 20–22°C for 24 h led to the formation of QR 6,8-dibromide (2) (52–54% yields, 96–98% purity by HPLC). Interaction of QR with 2–5 equiv. bromine in absolute ethanol at 0–5°C and 20–22°C for 24 h led to the formation of 3- O-ethyl-QR-2,3,6,8,5′-pentabromide (3) (95–97% purity by HPLC) the output of which depends on the quantity of bromine. It was shown in MDCK cell culture that compound 2 exhibits a moderate inhibitory activity against pandemic influenza virus A/H1N1/pdm09 (EC50 6.0 μg/mL, CTD50 97.7 μg/mL, SI 16). Compound 3 was inactive.