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. 2025 Apr 15;30(8):1776.
doi: 10.3390/molecules30081776.

6-Chlorocoumarin Conjugates with Nucleobases and Nucleosides as Potent Anti-Hepatitis C Virus Agents

Shu-Yu Lin  1 , Wen-Chieh Huang  1 , Shwu-Chen Tsay  2 , Johan Neyts  3 , Pieter Leyssen  3 , Chun-Cheng Lin  2 , Kuo Chu Hwang  2 , Jia-Cherng Horng  2 , Jih Ru Hwu  2
Affiliations

6-Chlorocoumarin Conjugates with Nucleobases and Nucleosides as Potent Anti-Hepatitis C Virus Agents

Shu-Yu Lin et al. Molecules. .

Abstract

On the basis of a "chemo-combination strategy", (6-chloro)coumarin was incorporated to purines and pyrimidines, as well as their corresponding nucleosides, with a -SCH2- linker at different positions under alkaline conditions. These conjugates were found to exert an antiviral effect on the 1b subgenomic replicon replication of the hepatitis C virus (HCV) in Huh 5-2 and Huh 9-13 cells. In this compound library containing 14 new compounds, 6-[(6'-chlorocoumarin-3'-yl)methylthio]purine, 6-(6'-chlorocoumarin-3'-yl)methylthio-9-(β-D-ribofuranos-1″-yl)purine, and 2-[(6'-chlorocoumarin-3'-yl)methylthio]uracil showed great inhibitory abilities, with EC50 values between 6.6 and 9.4 μM and selectivity indexes >16-41. Moreover, the structure-activity relationship between purines and pyrimidines is elucidated, which reveals the critical factor of the attachment of the coumarin moiety at different positions in purines and pyrimidines.

Keywords: coumarin; hepatitis C virus; mercaptopurine; nucleosides; structure–activity relationship.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Scheme 1
Scheme 1
Synthesis of “waist-type” coumarin–thioadenine/thioadenosine conjugates.
Scheme 2
Scheme 2
Synthesis of “waist-type” coumarin–thioguanine/thioguanosine conjugates.
Scheme 3
Scheme 3
Synthesis of “head-type” coumarin–thiopurine/thiopurine nucleoside conjugates.
Scheme 4
Scheme 4
Synthesis of “head-type” coumarin–thiopurine/thiopurine nucleoside conjugates.
Scheme 5
Scheme 5
Synthesis of “head-type” coumarin–thiouracil conjugates.
Scheme 6
Scheme 6
Synthesis of “head-type” coumarin–thiopyrimidine/thiopyrimidine nucleoside conjugates.
Scheme 7
Scheme 7
Synthesis of “tail-type” coumarin–thiopyrimidine conjugates.
Scheme 8
Scheme 8
A plausible mechanistic pathway for the covalent inhibition of the viral protease by the coumarin–thiopyrimidine conjugate 18.
See this image and copyright information in PMC

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