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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.

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.