The medicinal chemistry of Chikungunya virus

Abstract

Arthropod-borne viruses (arboviruses) are an important threat to human and animal health globally. Among these, zoonotic diseases account for billions of cases of human illness and millions of deaths every year, representing an increasing public health problem. Chikungunya virus belongs to the genus Alphavirus of the family Togariridae, and is transmitted mainly by the bite of female mosquitoes of the Aedes aegypti and/or A. albopictus species. The focus of this review will be on the medicinal chemistry of Chikungunya virus, including synthetic and natural products, as well as rationally designed compounds.

Keywords: Chikungunya; In silico; Medicinal chemistry; Natural products; Synthesis.

Graphical abstract

Fig. 1

Morphological visualization for Chikungunya virus, E₁ and E₂ proteins, genome length, and mutation in the Alanine residue.

Fig. 2

Chloroquine (1) chemical structure.

Fig. 3

Arbidol (2) and its sulfone (3) and sulfoxide (4) metabolites investigated by Delogu et al.

Fig. 4

Epigallocatechin gallate (91) chemical structure.

Fig. 5

The chemical structures of tannic acid and its derivatives.

Fig. 6

Harringtonine (103) chemical structure.

Fig. 7

Chemical structure of quinine (106).

Fig. 8

In silico predicted CHIKV nsP₂ inhibitors.

Fig. 9

Chemical structures of the CHIKV inhibitors identified from in silico screening.

Fig. 10

Compound (113) in complex with nsP₂ protein from Chikungunya virus.

Fig. 11

3D-view showing the interaction of compound (71) with CHIKV nsP₂ protease active site. In orange: hydrophobic contacts; in green: hydrogen-bond (value in Ångström).

Fig. 12

Chemical structure of Doxycycline (137).

Fig. 13

Chemical structure of Mycophenolic acid (138).

Fig. 14

Chemical structure of 6-Azauridine (139).

Fig. 15

Chemical structures of apigenin (193), chrysin (194), silybin (195), and luteolin (196) flavonoids.

Fig 16

Chemical structures of fisetin (197) and quercetagetin (198) flavonols.

Fig. 17

Chemical structure of anthraquinone ARDP0006 (199).

Fig. 18

Chemical structure of lanatoside C (200).

Fig. 19

Chemical structure of dec-RVKR-cmk (205).

Fig. 20

The structure of the dsRNA analog (215).

Fig. 21

Chemical structures of 6-Mercaptopurine (224) and azathioprine (225).

Fig. 22

Compounds isolated from S. lineata ssp. lineata stem bark.

Fig. 23

Chemical structures of lupenone (286) and β-amyrone (287) extracted from A. pervilleana.

Fig. 24

Purine-Based Inhibitors with Anti-CHIKV activity.

Scheme 1

The synthetic route for obtaining of arylhydrazone esters performed by Bandyopadhyay et al. Reagents and conditions: (i): NaNO₂/HCl, 0 → 5 °C; (ii) H₃CCOONa/H₃CCH₂OH.