Glycyrrhetinic acid derivatives as Zika virus inhibitors: Synthesis and antiviral activity in vitro

Lidia A Baltina; Hsueh-Chou Lai; Ya-Chi Liu; Su-Hua Huang; Mann-Jen Hour; Lia A Baltina; Tagir R Nugumanov; Sophia S Borisevich; Leonard M Khalilov; Svetlana F Petrova; Sergey L Khursan; Cheng-Wen Lin

doi:10.1016/j.bmc.2021.116204

Glycyrrhetinic acid derivatives as Zika virus inhibitors: Synthesis and antiviral activity in vitro

Bioorg Med Chem. 2021 Jul 1:41:116204. doi: 10.1016/j.bmc.2021.116204. Epub 2021 May 10.

Authors

Affiliations

¹ Ufa Institute of Chemistry, Ufa Federal Research Centre of the Russian Academy of Sciences, 71 prosp. Oktyabrya, 450054 Ufa, Russian Federation. Electronic address: baltina@anrb.ru.
² Division of Hepato-gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung 40447, Taiwan, ROC.
³ Department of Medical Laboratory Science and Biotechnology, China Medical University, 91, Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC; Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan, ROC.
⁴ Department of Biotechnology, Asia University, 500, Lioufeng Rd., Wufeng, Taichung 41354, Taiwan, ROC.
⁵ School of Pharmacy, China Medical University, Taichung 40402, Taiwan, ROC.
⁶ Ufa Institute of Chemistry, Ufa Federal Research Centre of the Russian Academy of Sciences, 71 prosp. Oktyabrya, 450054 Ufa, Russian Federation.
⁷ Institute of Petrochemistry and Catalysis, Ufa Federal Research Centre of the Russian Academy of Sciences, 141 prosp. Oktyabrya, 450054 Ufa, Russian Federation.
⁸ Department of Medical Laboratory Science and Biotechnology, China Medical University, 91, Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC; Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan, ROC; Department of Biotechnology, Asia University, 500, Lioufeng Rd., Wufeng, Taichung 41354, Taiwan, ROC. Electronic address: cwlin@mail.cmu.edu.tw.

PMID: 34022526
DOI: 10.1016/j.bmc.2021.116204

Abstract

Zika virus (ZIKV) is an arbovirus of the Flaviviridae family (Flavivirus genus), causing serious neurological complications, such as Guillain-Barre Syndrome (GBS) in adults and fetal microcephaly. Licensed vaccines or specific antiviral agents against ZIKV do not currently exist. Therefore, the search and development of anti-ZIKV agents are particularly relevant and necessary. Glycyrrhetinic (3β-hydroxy-11-oxo-18βH-Olean-12-en-30-oic acid) (GA) 1 is one of the well-known pentacyclic triterpenoids isolated from licorice root (Glycyrrhiza glabra L., Gl. uralensis Fisher) (Leguminosae) possessing many biological features, including antiviral activity. This paper is devoted to the synthesis and studies of a number of nitrogen and sulfur-containing GA derivatives as ZIKV inhibitors. Sixteen GA and related triterpenoids (3β-hydroxy-18βH-Olean-12-en-30-oic acid and 3β-hydroxy-11-oxo-18βH-Olean-12(13),18(19)-dien-30-oic acid) derivatives were synthesized (amides, semi- and thiosemicarbazones, and 1,2,3-thiadiazoles) and antiviral activity against ZIKV was studied in vitro, including the inhibitory assays on cytopathic effect (CPE), viral protein synthesis, and replication stages. Four active compounds were found among GA derivatives tested, 13 (3-O-acetyl-30-aminopyridine GA), 16 (3-semicarbazone-30-butyl GA), 18 (1,2,3-thiadiazole-30-methyl GA), and 19 (1,2,3-thiadiazole-30-butyl GA) with IC₅₀ < 1 μM against ZIKV replication. These compounds had a stronger inhibitory activity on ZIKV-induced CPE and viral protein translation in infected cells as compared to derivatives of 11-desoxo-GA. The most active compound was amide 13 (IC₅₀ 0.13 μM, TI ˃ 384). Time-of-addition assays indicated that 1,2,3-thiadiazole ring is important for inhibiting viral entry stage (compounds 18 and 19), while the 30-butyl ester group influenced on post-entry stage (compound 19). The molecular docking analysis demonstrated that lead compounds 13 and 19 forms a hydrogen-bond interaction with the catalytic triad (His51-Asp75-Ser135) of ZIKV NS2B-NS3 protease. Therefore, the active GA derivatives are promising for developing new antiviral agents against ZIKV infection.

Keywords: Derivatives; Glycyrrhetinic acid; Inhibitors; Synthesis; Triterpenoids; Zika virus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antiviral Agents / pharmacology*
Cell Line
Cell Survival / drug effects
Cricetinae
Gene Expression Regulation, Viral / drug effects
Glycyrrhetinic Acid / analogs & derivatives*
Glycyrrhetinic Acid / chemical synthesis
Glycyrrhetinic Acid / pharmacology*
Humans
Molecular Docking Simulation
Viral Proteins / genetics
Viral Proteins / metabolism
Zika Virus / drug effects*
Zika Virus Infection / drug therapy*

Substances

Antiviral Agents
Viral Proteins
Glycyrrhetinic Acid