PhSeZnCl in the Synthesis of Steroidal β-Hydroxy-Phenylselenides Having Antibacterial Activity

Jastrzębska, Izabella; Mellea, Stefano; Salerno, Valerio Mario; Grzes, Pawel A.; Siergiejczyk, Leszek; Niemirowicz-Laskowska, Katarzyna; Bucki, Robert; Monti, Bonifacio; Santi, Claudio

doi:10.3390/ijms20092121

Cited by 14 publications

(10 citation statements)

References 41 publications

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“…Considering our interest in the synthesis of organoselenium compounds with antioxidant activity, in light of the above-reported evidence and in the frame of our efforts to develop antimicrobial compounds [15][16][17][18], we sought to prepare novel quercetin derivatives decorated with organochalcogen moieties. These new hybrid compounds could present improved M pro inhibition and be endowed with the ability to hamper SARS-CoV-2 replication in a cellular context, thus being suitable to be considered for preclinical studies required for the development of direct antiviral agents.…”

Section: Introductionmentioning

confidence: 99%

Seleno-Functionalization of Quercetin Improves the Non-Covalent Inhibition of Mpro and Its Antiviral Activity in Cells against SARS-CoV-2

Mangiavacchi

Botwina

Menichetti

et al. 2021

IJMS

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The development of new antiviral drugs against SARS-CoV-2 is a valuable long-term strategy to protect the global population from the COVID-19 pandemic complementary to the vaccination. Considering this, the viral main protease (Mpro) is among the most promising molecular targets in light of its importance during the viral replication cycle. The natural flavonoid quercetin 1 has been recently reported to be a potent Mpro inhibitor in vitro, and we explored the effect produced by the introduction of organoselenium functionalities in this scaffold. In particular, we report here a new synthetic method to prepare previously inaccessible C-8 seleno-quercetin derivatives. By screening a small library of flavonols and flavone derivatives, we observed that some compounds inhibit the protease activity in vitro. For the first time, we demonstrate that quercetin (1) and 8-(p-tolylselenyl)quercetin (2d) block SARS-CoV-2 replication in infected cells at non-toxic concentrations, with an IC50 of 192 μM and 8 μM, respectively. Based on docking experiments driven by experimental evidence, we propose a non-covalent mechanism for Mpro inhibition in which a hydrogen bond between the selenium atom and Gln189 residue in the catalytic pocket could explain the higher Mpro activity of 2d and, as a result, its better antiviral profile.

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Section: Introductionmentioning

confidence: 99%

Seleno-Functionalization of Quercetin Improves the Non-Covalent Inhibition of Mpro and Its Antiviral Activity in Cells against SARS-CoV-2

Mangiavacchi

Botwina

Menichetti

et al. 2021

IJMS

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“…2022, 23, x FOR PEER REVIEW 3 of 11 diphenyldiselenide (PhSe)2 and other, differently functionalized diselenides [11]. This chemistry was expanded at different positions within the steroidal core by some of us who recently reported the epoxide transformation exploiting the reactivity of PhSeZnCl, obtaining selenosteroids endowed with antibiofilm activity [12,13].…”

Section: Resultsmentioning

confidence: 99%

Simple Zn-Mediated Seleno- and Thio-Functionalization of Steroids at C-1 Position

Grzes

Monti

Wawrusiewicz‐Kurylonek

et al. 2022

IJMS

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Here we report the reaction in the biphasic system of the in situ prepared selenols and thiols with 1,4-androstadiene-3,17-dione (1) or prednisone acetate (2) having α,β-unsaturated ketone as an electrophilic functionalization. The Michael-type addition reaction resulted to be chemo- and stereoselective, affording a series of novel steroidal selenides and sulfides. This is an example of a one-step, eco-friendly process that bypasses some of the main concerns connected with the bad smell and the toxicity of these seleno- and thio-reagents. Furthermore, we demonstrated that the proposed methodology offers the possibility to prepare libraries of steroids variously and selectively decorated with different organochalcogen moieties at the C1 position starting from 1,4-androstadienic skeletons and leaving unaltered the C4–C5 unsaturation. Based on the data reported in the literature the introduction of an organoselenium or an organosulfur moiety in a steroid could provide new interesting pharmaceutically active entities exerting anticancer and antimicrobial activities. In this optic, new synthetic strategies to efficiently prepare this class of compounds could be strongly desirable.

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“…Several studies have shown that selenium compounds such as thiaselenazoles, dithiazoles, and selenium–platinum complexes are effective antimicrobial and antiviral agents [ 9 , 10 , 11 , 12 , 13 ]. These agents allow for both narrow- and broad-spectrum antimicrobial and viral activity at micromolar concentrations with limited toxicity [ 9 , 10 , 11 , 12 , 13 ]. Furthermore, these agents are effective against multidrug-resistant bacteria and the formation of bacterial biofilms [ 9 , 10 , 11 , 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…These agents allow for both narrow- and broad-spectrum antimicrobial and viral activity at micromolar concentrations with limited toxicity [ 9 , 10 , 11 , 12 , 13 ]. Furthermore, these agents are effective against multidrug-resistant bacteria and the formation of bacterial biofilms [ 9 , 10 , 11 , 12 , 13 ]. An ideal antibacterial drug would target the virulence mechanisms of bacterial pathogens and not be affected by existing resistance mechanisms in these bacteria [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

The Use of an Organo-Selenium Peptide to Develop New Antimicrobials That Target a Specific Bacteria

et al. 2021

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This study examines the use of a covalently selenium-bonded peptide and phage that binds to the Yersinia pestis F1 antigen for the targeting and killing of E. coli expressing this surface antigen. Using a Ph.D.-12 phage-display library for affinity selection of the phage which would bind the F1 antigen of Y. pestis, a phage displaying a peptide that binds the F1 antigen with high affinity and specificity was identified. Selenium was then covalently attached to the display phage and the corresponding F1-antigen-binding peptide. Both the phage and peptides with selenium covalently attached retained their binding specificity for the Y. pestis F1 antigen. The phage or peptide not labeled with selenium did not kill the targeted bacteria, while the phage or peptide labeled with selenium did. In addition, the seleno-peptide, expressing the F1 targeting sequence only, killed cells expressing the F1 antigen but not the parent strain that did not express the F1 antigen. Specifically, the seleno-peptide could kill eight logs of bacteria in less than two hours at a 10-µM concentration. These results demonstrate a novel approach for the development of an antibacterial agent that can target a specific bacterial pathogen for destruction through the use of covalently attached selenium and will not affect other bacteria.

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PhSeZnCl in the Synthesis of Steroidal β-Hydroxy-Phenylselenides Having Antibacterial Activity

Cited by 14 publications

References 41 publications

Seleno-Functionalization of Quercetin Improves the Non-Covalent Inhibition of Mpro and Its Antiviral Activity in Cells against SARS-CoV-2

Seleno-Functionalization of Quercetin Improves the Non-Covalent Inhibition of Mpro and Its Antiviral Activity in Cells against SARS-CoV-2

Simple Zn-Mediated Seleno- and Thio-Functionalization of Steroids at C-1 Position

The Use of an Organo-Selenium Peptide to Develop New Antimicrobials That Target a Specific Bacteria

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