New chalcone derivatives: synthesis, antiviral activity and mechanism of action

Abstract

In this work, twenty-eight chalcone derivatives containing a purine (sulfur) ether moiety were synthesized and their antiviral activities were evaluated. Biological results showed that compound 5d exhibited outstanding inactive activity against tobacco mosaic virus (TMV) in vivo (EC₅₀ = 65.8 μg mL^-1), which is significantly superior to that of ribavirin (EC₅₀ = 154.3 μg mL^-1). Transmission electron microscopy indicated that compound 5d can break the integrity of TMV particles. The results of microscale thermophoresis, fluorescence titration and molecular docking showed that compound 5d had stronger combining affinity (K _a = 1.02 ×10⁵ L mol^-1, K _d = 13.4 μmol L^-1) with TMV coat protein (TMV-CP), which is due to the formation of five hydrogen bonds between compound 5d and the amino-acid residues of TMV-CP. These findings revealed that compound 5d can effectively inhibit the infective ability of TMV. This work provides inspiration and reference for the discovery of new antiviral agents.

Fig. 1. Design strategy of the title compounds.

Scheme 1. The synthetic route of the target compounds 4a–4f and 5a–5l.

Scheme 2. The synthetic route of the target compounds 7a–7e and 8a–8e.

Fig. 2. The EC₅₀ curve of the compound 5d (a) and ribavirin (b), inhibitory activity = 5 + NORMSINV(inhibition ratio).

Fig. 3. The morphology changes of TMV particles treated with the compounds, CK (A), ribavirin + TMV (B) and 5d + TMV (C).

Fig. 4. The FT measurement results of compounds 5d (A), 5g (B), 5k (C) and ribavirin (D) to TMV-CP.

Fig. 5. The MST measurement results of compounds 5d (A), 5g (B), 5k (C) and ribavirin (D) to TMV-CP.

Fig. 6. The binding models of the compounds 5d (A), 5g (B), 5k (C) and ribavirin (D) to TMV-CP.