Chikungunya virus inhibition by synthetic coumarin-guanosine conjugates

Jih Ru Hwu; Wen-Chieh Huang; Shu-Yu Lin; Kui-Thong Tan; Yu-Chen Hu; Fa-Kuen Shieh; Sergey O Bachurin; Alexey Ustyugov; Shwu-Chen Tsay

doi:10.1016/j.ejmech.2019.01.037

Chikungunya virus inhibition by synthetic coumarin-guanosine conjugates

Eur J Med Chem. 2019 Mar 15:166:136-143. doi: 10.1016/j.ejmech.2019.01.037. Epub 2019 Jan 21.

Authors

Jih Ru Hwu¹, Wen-Chieh Huang², Shu-Yu Lin², Kui-Thong Tan², Yu-Chen Hu³, Fa-Kuen Shieh⁴, Sergey O Bachurin⁵, Alexey Ustyugov⁵, Shwu-Chen Tsay⁶

Affiliations

¹ Department of Chemistry, National Tsing Hua University, Hsinchu, 300, Taiwan; Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, 300, Taiwan; Department of Chemistry, National Central University, Jhongli City, Taoyuan, 320, Taiwan. Electronic address: jrhwu@mx.nthu.edu.tw.
² Department of Chemistry, National Tsing Hua University, Hsinchu, 300, Taiwan; Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, 300, Taiwan.
³ Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, 300, Taiwan; Department of Chemical Engineering, National Tsing Hua University, Hsinchu, 300, Taiwan.
⁴ Department of Chemistry, National Central University, Jhongli City, Taoyuan, 320, Taiwan.
⁵ The Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, 142432, Russia.
⁶ Department of Chemistry, National Tsing Hua University, Hsinchu, 300, Taiwan; Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, 300, Taiwan; Department of Chemistry, National Central University, Jhongli City, Taoyuan, 320, Taiwan. Electronic address: sctsay@mx.nthu.edu.tw.

PMID: 30703657
DOI: 10.1016/j.ejmech.2019.01.037

Abstract

Since its discovery in Tanganyika, Africa in 1952, chikungunya virus (CHIKV) outbreaks have occurred in Africa, Asia, Europe, and America. Till now chikungunya fever has spread in nearly 40 countries. Because of lack of effective vaccines and antiviral drugs to intervene this disease, 21 new conjugated compounds were designed and synthesized by coupling of 6,8-dithioguanosine at its C-6 position with 3-(chloromethyl)coumarins bearing an F, Cl, Br, Me, or -OMe substituent through the -SCH₂- joint. Meanwhile, an organic "dummy" ligand (e.g., methyl, benzyl, and naphthylmethyl) or a coumarinyl moiety was attached at the C-8 position. By high through-put screening, three of these new conjugates were found to inhibit CHIKV in Vero cells with significant potency (EC₅₀ = 9.9-13.9 μM) and showed low toxicity (CC₅₀ = 96.5-212 μM). The selectivity index values were 9.37-21.7. Their structure-activity relationship was deduced, which indicates that the coumarin moiety is essential and the presence of a -OMe group enhances the antiviral activity.

Keywords: Chikungunya virus; Conjugate; Coumarin; Guanosine; Thiomethylene.

MeSH terms

Animals
Antiviral Agents / chemistry*
Antiviral Agents / pharmacology*
Chikungunya virus / drug effects*
Chlorocebus aethiops
Coumarins / chemistry*
Guanosine / chemistry*
Guanosine / pharmacology*
Hydrophobic and Hydrophilic Interactions
Inhibitory Concentration 50
Vero Cells

Substances

Antiviral Agents
Coumarins
Guanosine
coumarin