Aurones: A Promising Scaffold to Inhibit SARS-CoV-2 Replication

Abstract

Aurones are a small subgroup of flavonoids in which the basic C6–C3–C6 skeleton is arranged as (Z)-2-benzylidenebenzofuran-3(2H)-one. These compounds are structural isomers of flavones and flavonols, natural products reported as potent inhibitors of SARS-CoV-2 replication. Herein, we report the design, synthesis, and anti-SARS-CoV-2 activity of a series of 25 aurones bearing different oxygenated groups (OH, OCH3, OCH2OCH3, OCH2O, OCF2H, and OCH2C6H4R) at the A- and/or B-rings using cell-based screening assays. We observed that 12 of the 25 compounds exhibit EC50 < 3 μM (8e, 8h, 8j, 8k, 8l, 8m, 8p, 8q, 8r, 8w, 8x, and 8y), of which five presented EC50 < 1 μM (8h, 8m, 8p, 8q, and 8w) without evident cytotoxic effect in Calu-3 cells. The substitution of the A- and/or B-ring with OCH3, OCH2OCH3, and OCF2H groups seems beneficial for the antiviral activity, while the corresponding phenolic derivatives showed a significant decrease in the anti-SARS-CoV-2 activity. The most potent compound of the series, aurone 8q (EC50 = 0.4 μM, SI = 2441.3), is 2 to 3 times more effective than the polyphenolic flavonoids myricetin (2) and baicalein (1), respectively. Investigation of the five more active compounds as inhibitors of SARS-CoV-2 3CLpro based on molecular dynamic calculations suggested that these aurones should detach from the active site of 3CLpro, and, probably, they could bind to another SARS-CoV-2 protein target (either receptor or enzyme).

Synthesis and evaluation of hybrid sulfonamide‐chalcones with potential antileishmanial activity

“…The synthetic route to prepare sulfonamide-chalcones derivatives 10a-h involved the synthetic intermediate amino-chalcone (11), and the amide-chalcones (12) are shown in Scheme 1. The first step consisted of preparing the lead compound NAT22 (6), a nitrochalcone, in 91% yield, from a Claisen-Schmidt condensation reaction between the 2′,4′,6′-trimethoxy-acetophenone (13) and the 3-nitrobenzaldehyde (14) in the presence of a basic catalyst.…”

“…[35,36] That was followed by the reduction of the nitro substituent to an amine using Fe 0 as the reducing agent to generate the synthetic intermediate amino-chalcone (11), with a 95% yield. [37] This intermediate aminochalcone (11) was also used to analyze the effect of the sulfonyl group on the antileishmanial activity. In the last step to generate the sulfonamide-chalcones derivatives (10a-h) with good yields (71%-96%), the usual synthetic strategy was used, which involves the formation of the new N-S bond by using the amino-chalcone (11) and aryl-or benzyl-sulfonyl chloride (15) in a 1:1 ratio.…”

“…The first step consisted of preparing the lead compound NAT22 (6), a nitrochalcone, in 91% yield, from a Claisen-Schmidt condensation reaction between the 2′,4′,6′-trimethoxy-acetophenone (13) and the 3-nitrobenzaldehyde (14) in the presence of a basic catalyst. [35,36] That was followed by the reduction of the nitro substituent to an amine using Fe 0 as the reducing agent to generate the synthetic intermediate amino-chalcone (11), with a 95% yield. [37] This intermediate aminochalcone (11) was also used to analyze the effect of the sulfonyl group on the antileishmanial activity.…”

“…F I G U R E 3 The rational approach to the design of novel arylsulfonamide-chalcones (10a-h), amine-chalcone (11), and arylamidechalcone (12).…”

“…[9] This NP is a biosynthetic intermediary of three different cyclic flavonoids. [10,11] Over the years, chalcones have been studied for their biological properties, such as anticancer [12,13] antimicrobial, [14] anti-inflammatory, [15] antiviral, [16,17] antimalarial, [18] and particularly their antileishmanial activity. [19] The first natural chalcone shown to have antileishmanial activity was the licochalcone A (2, Figure 1) isolated from the Glycyrrhiza glabra plant in the 1990s which exhibited growth inhibition against the promastigote form of Leishmania major and Leishmania donovani species (IC 50 = 7.0 µM).…”