Synthesis and Antiviral Activity of Amino-Acid Conjugates of Glycyrrhetic Acid

Abstract

Conjugates of glycyrrhetic acid (GLA) with amino acids (L-isoleucine, -leucine, -valine, and -phenylalanine) were synthesized by the acid-chloride method using methyl or tert-butyl esters of the acids. Tests in MDCK cell culture showed that the GLA conjugate with phenylalanine exhibited high antiviral activity against influenza A/H1N1/pdm09 virus (ED 50 =4.4 Pg/mL, SI = 161).Chemical modification of plant triterpenoids has in the last decade produced a whole series of lead compounds that are medically promising as new antitumor, antiviral, and antidiabetic agents.The pentacyclic triterpenoid glycyrrhetic acid (GLA, 1) is the product from acid and enzymatic hydrolysis of glycyrrhizic acid, the principal constituent of Glycyrrhiza glabra L. and G. uralensis Fisher roots, and is a promising natural product for creating new drugs to treat and prevent oncological and inflammatory diseases, hepatoprotectors, antioxidants, antiulcer and antiviral agents, etc.[1]. The potential to produce new biologically active compounds through chemical modification of GLA has not been fully explored [2][3][4][5].In continuation of our research on the synthesis of new biologically active GLA derivatives, we synthesized aminoacid conjugates using GLA 3-O-acetate (2) as starting material. It was converted into acid chloride 3 via reaction with thionylchloride (SOCl 2 ) in benzene (Scheme 1). The amino acids were methyl or tert-butyl (t-Bu) esters of L-amino acid hydrochlorides and were acylated via reaction with 3 in CH 2 Cl 2 in the presence of Et 3 N or N-methylmorpholine (NMM) to afford conjugates 4-8 in 60-70% yields. The yields of the protected conjugates were higher if the amino-acid t-Bu esters were used as the amines.Analytically pure 4 and 5 were isolated by column chromatography (CC) over silica gel (SG). Conjugates 6-8 were reprecipitated from aqueous EtOH. The protecting groups were removed without further purification.Conjugates 4 and 5 in dioxane:MeOH were treated with aqueous NaOH (4 N) and acidified subsequently with HCl solution (5%) in order to remove the 3-O-acetyl and methyl ester. The t-Bu ester protecting group of 6-8 was removed by trifluoroacetic acid (TFA) in CH 2 Cl 2 at 20-22°C. Then, the 3-O-acetyl protection was removed in dioxane by alkaline hydrolysis using aqueous NaOH (4 N). The resulting compounds were chromatographed over SG to afford free GLA conjugates 9-12 containing free amino acids L-isoleucine (Ile), -leucine (Leu), -valine (Val), and -phenylalanine (Phe) in 53-57% yields.

Development of anti‐influenza agents from natural products

“…Correspondingly, Baltina and co‐workers synthesized and evaluated some GL derivatives against the pandemic influenza A/H1N1/pdm09 virus. Compound 67 , the conjugate of GLA with phenylalanine, exhibited significant inhibitory activity (EC 50 = 5.3 μM, CTD 50 = 860.0 μM, SI = 161) against this virus 78 . Compounds 68–73 are the synthetic amino acid methyl ester derivatives of GL, and the most active inhibitors against influenza A/H1N1/pdm09 were 71 (phenylalanine, EC 50 = 4.3 µM, SI = 61), 72 (tyrosine, EC 50 = 6.8 µM, SI = 38), and 73 ( S ‐benzyl‐cysteine, EC 50 = 3.5 µM, SI = 71).…”

Antiviral opportunities of Mannich bases derived from triterpenic N‐propargylated indoles

“…The antiviral activity of glycyrrhetic acid and its derivatives has been revealed against various DNA and RNA viruses (Shinu et al, 2023). Among the amino acid conjugates of glycyrrhetic acid, effective inhibitors of influenza A/H1N1 virus have been found (Baltina et al, 2014), while the derivatives with aromatic substituents at C30 position are highly active against hepatitis B virus (Wang et al, 2012). Amides, semi-and thiosemicarbazones, and 1,2,3-thiadiazoles of glycyrrhetic acid were effective as inhibitors of ZIKV-induced cytopathic effect, viral NS1 production, and infectivity of ZIKV with IC 50 < 1 μM (Baltina et al, 2021).…”

Untitled

“…The molecular formula of GA is C 30 H 46 O 4 , and its structural formula is shown in fig1. Studies have shown that GA has anti-inflammatory, antiviral, antitumor and analgesic effects (Khudobko et al, 2014, Liu et al, 2019, Chen et al, 2019, Zhao et al, 2013. However, glycyrrhetinic acid has extremely poor solubility in water and low bioavailability, which limits its oral bioavailability (Dai et al, 2019).…”