Therapeutic potential of coumarins as antiviral agents

Abstract

Coumarins have received a considerable attention in the last three decades as a lead structures for the discovery of orally bioavailable non-peptidic antiviral agents. A lot of structurally diverse coumarins analogues were found to display remarkable array of affinity with the different molecular targets for antiviral agents and slight modifications around the central motif result in pronounced changes in its antiviral spectrum. This manuscript thoroughly reviews the design, discovery and structure-activity relationship studies of the coumarin analogues as antiviral agents focusing mainly on lead optimization and its development into clinical candidates.

Keywords: Anti-HCV; Anti-HIV; Anti-herpes; Anti-influenza; Antiviral; Coumarin.

Graphical abstract

Fig. 1

Different classes of coumarins effective against various viral diseases.

Fig. 2

Replacement of α-acetonyl with ethyl group led to weak HIV protease inhibitory activity but better pharmacokinetic.

Fig. 3

Docked structure of phenprocoumon at the active site of HIV-1 protease (PDB ID: 1UPJ) and schematic representation of 4-HC pharmacophore.

Fig. 4

Structure-based design of 4-hydroxy-2-pyrone as a first clinical candidate against HIV protease.

Fig. 5

Structure-based design of hybrid carboxamide derivatives of 4-hydroxycoumarins.

Fig. 6

General structure-activity relationship (SAR) of 4-hydroxycoumarins as HIV protease inhibitors.

Fig. 7

Conformationally flexible analogues of 4-hydroxycoumarins.

Fig. 8

4-hydroxycoumarins and related pyrones developed by Parke-Davis.

Fig. 9

Dimers and tetramers of 4-hydroxycoumarins as dual integrase and reverse transcriptase inhibitors.

Fig. 10

3-Substituted-4-hydroxycoumarins as HIV-1 protease inhibitor.

Fig. 11

Tricyclic pyranocoumarins: Khellactones as anti-HIV-1 agents.

Fig. 12

Tetracyclic dipyranocoumarins as HIV-1 reverse transcriptase inhibitors.

Fig. 13

Natural furanocoumarins as potential anti-HIV agents.

Fig. 14

3-Phenylcoumarins as potential candidate for anti-HIV agents.

Fig. 15

Anti-HIV agent vipirinin acting through novel mechanism.

Fig. 16

Isoprenylated coumarins as HIV-1 inhibitors.

Fig. 17

Hybrid coumarin derivatives as potent anti-HIV agents.

Fig. 18

Miscellaneous natural anti-HIV coumarins.

Fig. 19

Coumarin-benzimidazole conjugates linked directly or through linker.

Fig. 20

Imidazopyridine based coumarin NS5B inhibitors.

Fig. 21

Novel anilinocoumarin derivatives as anti-HCV agents.

Fig. 22

7-Hydroxycoumarin derivatives as anti-HCV and anti-HBV agents.

Fig. 23

Coumestans analogues as novel potent NS5B inhibitors.

Fig. 24

Angelicin derivatives as dual anti-influenza and anti-HIV agents.

Fig. 25

Different plant based coumarin compounds effective against herpes viruses.

Fig. 26

Hydroxycoumarin derivatives possessing inhibitory activity against HSV.

Fig. 27

Uracil containing coumarin derivatives as chikungunya virus inhibitors.

Fig. 28

7-Diethylamino coumarins effective against chikungunya virus.