Usnic acid based thiazole-hydrazones as multi-targeting inhibitors of a wide spectrum of SARS-CoV-2 viruses

Yarovaya, Olga I.; Filimonov, Aleksandr S.; Baev, Dmitriy S.; Borisevich, Sophia S.; Chirkova, Varvara Yu.; Zaykovskaya, Anna V.; Mordvinova, Ekaterina D.; Belenkaya, Svetlana V.; Shcherbakov, Dmitriy N.; Luzina, Olga A.; Pyankov, Oleg V.; Salakhutdinov, Nariman F.

doi:10.1039/d3nj03598k

Cited by 2 publications

(4 citation statements)

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“…A number of studies involving virtual screening approaches [ 47 , 48 , 49 ] and our own data [ 25 ] indicate that the SARS-CoV-2 main protease can be a target for usnic-acid derivatives. Previously, we synthesized a set of thiazolo-hydrazones based on (+)- and (−)-usnic acid containing furan, pyrrole, indole, or p-methoxybenzylidene derivatives with different substituents at the m -position and investigated their ability to inhibit the main viral protease of SARS-CoV-2 [ 25 ]. Nine of 36 drugs were found to exhibit antiprotease activity in the range of 13 to 27 µM.…”

Section: Resultsmentioning

confidence: 99%

“…Nine of 36 drugs were found to exhibit antiprotease activity in the range of 13 to 27 µM. Kinetic parameters of the four most active compounds were studied, and molecular modeling of the possible interaction of these compounds with the active site of the main protease was carried out [ 25 ]. At the same time, we noticed that the most active furan derivatives are not stable during storage.…”

Section: Resultsmentioning

confidence: 99%

“…A number of studies involving virtual screening approaches [47][48][49] and our own data [25] indicate that the SARS-CoV-2 main protease can be a target for usnic-acid derivatives. Previously, we synthesized a set of thiazolo-hydrazones based on (+)-and ()-usnic acid containing furan, pyrrole, indole, or p-methoxybenzylidene derivatives As a result, we prepared a set of derivatives based on (+)-and (−)-usnic acid containing unsubstituted thiophenes or methyl-, bromo-, or nitrothiophenes.…”

Section: Enzymatic Inhibition Assays With Sars-cov-2 3cl Promentioning

confidence: 87%

“…Previously, it has been demonstrated that usnic acid is active against different coronavirus strains [ 24 ]. We recently found that thiazohydrazones based on (+)- and (−)-usnic acid containing furan moieties, pyrrole moieties, or indole moieties, as well as p-methoxybenzylidene derivatives with various substituents at the m -position, possess activity against the main viral protease [ 25 ]. Compounds containing a furan moiety have demonstrated the highest activity against both proteases and infectious viruses.…”

Section: Introductionmentioning

confidence: 99%

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The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 Viruses

Yarovaya,

Filimonov,

Baev

et al. 2024

Viruses

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Although the COVID-19 pandemic caused by SARS-CoV-2 viruses is officially over, the search for new effective agents with activity against a wide range of coronaviruses is still an important task for medical chemists and virologists. We synthesized a series of thiazolo-thiophenes based on (+)- and (−)-usnic acid and studied their ability to inhibit the main protease of SARS-CoV-2. Substances containing unsubstituted thiophene groups or methyl- or bromo-substituted thiophene moieties showed moderate activity. Derivatives containing nitro substituents in the thiophene heterocycle—just as pure (+)- and (−)-usnic acids—showed no anti-3CLpro activity. Kinetic parameters of the most active compound, (+)-3e, were investigated, and molecular modeling of the possible interaction of the new thiazolo-thiophenes with the active site of the main protease was carried out. We evaluated the binding energies of the ligand and protein in a ligand–protein complex. Active compound (+)-3e was found to bind with minimum free energy; the binding of inactive compound (+)-3g is characterized by higher values of minimum free energy; the positioning of pure (+)-usnic acid proved to be unstable and is accompanied by the formation of intermolecular contacts with many amino acids of the catalytic binding site. Thus, the molecular dynamics results were consistent with the experimental data. In an in vitro antiviral assay against six strains (Wuhan, Delta, and four Omicron sublineages) of SARS-CoV-2, (+)-3e demonstrated pronounced antiviral activity against all the strains.

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