Ebsulfur and Ebselen as highly potent scaffolds for the development of potential SARS-CoV-2 antivirals

Abstract

The emerging COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has raised a global catastrophe. To date, there is no specific antiviral drug available to combat this virus, except the vaccine. In this study, the main protease (M pro ) required for SARS-CoV-2 viral replication was expressed and purified. Thirty-six compounds were tested as inhibitors of SARS-CoV-2 M pro by fluorescence resonance energy transfer (FRET) technique. The half-maximal inhibitory concentration (IC 50 ) values of Ebselen and Ebsulfur analogs were obtained to be in the range of 0.074-0.91 μM. Notably, the molecules containing furane substituent displayed higher inhibition against M pro , followed by Ebselen 1i (IC 50 = 0.074 μM) and Ebsulfur 2k (IC 50 = 0.11 μM). The action mechanism of 1i and 2k were characterized by enzyme kinetics, pre-incubation and jump dilution assays, as well as fluorescent labeling experiments, which suggested that both compounds covalently and irreversibly bind to M pro , while molecular docking suggested that 2k formed an S–S bond with the Cys145 at the enzymatic active site. This study provides two very potent scaffolds Ebsulfur and Ebselen for the development of covalent inhibitors of M pro to combat COVID-19.

In silico Studies on the Interaction between Mpro and PLpro From SARS‐CoV‐2 and Ebselen, its Metabolites and Derivatives

“…In this sense, the data obtained herein confirm and extend the view that organoselenium molecules are an important class of compounds that should be further studied for their efficacy in inhibiting SARS-CoV-2 proteases. Furthermore, we suggest that ethaselen, ebselen diselenide, ebsulfur, and methylebselenoxide (which can be obtained from synthetic methodologies already described in the literature [106][107][108][109][110][111][112] ) should be tested in vitro as inhibitors of virus replication and its proteases.…”

Catalytic Antioxidant Activity of Bis-Aniline-Derived Diselenides as GPx Mimics

“…Of the aniline-derived diselenides, the highest catalytic efficiency was observed for compound 3b ( Table 1 , entry 4), which was 5 and 2 times more active than the standards ebselen and diphenyl diselenide, respectively. It is worth noting that the diselenide 3b was more effective than ebselen, which is a pre-clinical drug candidate with pronounced biological activities, including, recently, the inhibition of protease M pro from COVID-19 (SARS-CoV-2) virus [ 29 , 30 , 31 ].…”

“…These compounds have been recently described as good antioxidants [ 10 , 11 ], also presenting anti-inflammatory [ 12 , 13 ], antibacterial [ 14 ], antiviral [ 15 ], anticancer [ 16 , 17 , 18 , 19 ], anti-Alzheimer’s [ 20 , 21 , 22 , 23 ] and other activities [ 24 , 25 , 26 , 27 , 28 ]. Furthermore, in relation to the current pandemic of COVID-19, there are some interesting studies available that demonstrate the effectiveness of organoselenium compound (Ebselen) as an antiviral molecule, Figure 1 [ 29 , 30 , 31 ].…”

Ebselen and Analogues: Pharmacological Properties and Synthetic Strategies for Their Preparation

“…Weglarz-Tomczak et al reported a series of ebselen-like structures able to inhibit not only M pro , but also the other pivotal protease, a papain-like protease from SARS-CoV-2 with comparable potencies, in the high micromolar range [ 52 ]. Yang et al prepared a series of ebselen and ebsulfur (compound 23 , Figure 2 ) analogues variously functionalized at the nitrogen atom with aryl, alkyl, benzyl and heteroaryl substituent identifying compounds endowed with a better M pro activity when compared to the native lead compound; interestingly, not only ebselen but also 23 proved to covalently bind M pro [ 53 ]. It is worth mentioning that ebselen-like structures are always more potent when compared to their sulfur analogues.…”