Role of Group 12 Metals in the Reduction of H2O2 by Santi's Reagent: A Computational Mechanistic Investigation.

PhSeZnCl, which is also known as Santi's reagent, can catalyze the reduction of hydrogen peroxide by thiols with a GPx-like mechanism. In this work, the first step of this catalytic cycle, i.e., the reduction of H2O2 by PhSeZnCl, is investigated in silico using state-of-the-art density functional theory calculations. Then, the role of the metal is evaluated by replacing Zn with its group 12 siblings (Cd and Hg). The thermodynamic and kinetic factors favoring Zn are elucidated. Furthermore, the role of the halogen is considered by replacing Cl with Br in all three metal compounds, and this turns out to be negligible. Finally, the overall GPx-like mechanism of PhSeZnCl and PhSeZnBr is discussed by evaluating the energetics of the mechanistic path leading to the disulfide product.

Top Selling (2026) Small Molecule Orphan Drugs: A Journey into Their Chemistry.

This review describes, from a chemical point of view, the top "blockbuster" small molecule orphan drugs according to their forecasted sales in 2026. Orphan drugs are intended for the treatment, prevention, or diagnosis of a rare disease or condition. These molecules are mostly addressed to the treatment of rare forms of cancer. The respiratory and central nervous systems represent other common therapeutic subcategories. This work will show how the orphan drugs market has significantly grown and will account for a consistent part of prescriptions by 2026.

Visible light photocatalysis in the late-stage functionalization of pharmaceutically relevant compounds.

The late stage functionalization (LSF) of complex biorelevant compounds is a powerful tool to speed up the identification of structure-activity relationships (SARs) and to optimize ADME profiles. To this end, visible-light photocatalysis offers unique opportunities to achieve smooth and clean functionalization of drugs by unlocking site-specific reactivities under generally mild reaction conditions. This review offers a critical assessment of current literature, pointing out the recent developments in the field while emphasizing the expected future progress and potential applications. Along with paragraphs discussing the visible-light photocatalytic synthetic protocols so far available for LSF of drugs and drug candidates, useful and readily accessible synoptic tables of such transformations, divided by functional groups, will be provided, thus enabling a useful, fast, and easy reference to them.

New Insights into Green Protocols for Oxidative Depolymerization of Lignin and Lignin Model Compounds.

Oxidative depolymerization of lignin is a hot topic in the field of biomass valorization. The most recent and green procedures have been herein detailed. Photochemical and electrochemical approaches are reviewed highlighting the pros and cons of each method. Mechanochemistry activated strategies are able to combine oxidation and depolymerization in the deconstruction of lignin. Homogenous and heterogeneous catalytic systems are exemplified stressing the green aspects associated with both the procedures. Solvent-free approaches as well as those carried out in alternative media are listed. Finally, the few examples of selenium catalyzed lignin valorization reported so far are cited.

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

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,ß-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.

New Halogen-Containing Drugs Approved by FDA in 2021: An Overview on Their Syntheses and Pharmaceutical Use.

This review describes the recent Food and Drug Administration (FDA)-approved drugs (in the year 2021) containing at least one halogen atom (covalently bound). The structures proposed throughout this work are grouped according to their therapeutical use. Their synthesis is presented as well. The number of halogenated molecules that are reaching the market is regularly preserved, and 14 of the 50 molecules approved by the FDA in the last year contain halogens. This underlines the emergent role of halogens and, in particular, of fluorine and chlorine in the preparation of drugs for the treatment of several diseases such as viral infections, several types of cancer, cardiovascular disease, multiple sclerosis, migraine and inflammatory diseases such as vasculitis.

"Green Is the Color": An Update on Ecofriendly Aspects of Organoselenium Chemistry.

Organoselenium compounds have been successfully applied in biological, medicinal and material sciences, as well as a powerful tool for modern organic synthesis, attracting the attention of the scientific community. This great success is mainly due to the breaking of paradigm demonstrated by innumerous works, that the selenium compounds were toxic and would have a potential impact on the environment. In this update review, we highlight the relevance of these compounds in several fields of research as well as the possibility to synthesize them through more environmentally sustainable methodologies, involving catalytic processes, flow chemistry, electrosynthesis, as well as by the use of alternative energy sources, including mechanochemical, photochemistry, sonochemical and microwave irradiation.

Flow Biocatalysis: A Challenging Alternative for the Synthesis of APIs and Natural Compounds.

Biocatalysts represent an efficient, highly selective and greener alternative to metal catalysts in both industry and academia. In the last two decades, the interest in biocatalytic transformations has increased due to an urgent need for more sustainable industrial processes that comply with the principles of green chemistry. Thanks to the recent advances in biotechnologies, protein engineering and the Nobel prize awarded concept of direct enzymatic evolution, the synthetic enzymatic toolbox has expanded significantly. In particular, the implementation of biocatalysts in continuous flow systems has attracted much attention, especially from industry. The advantages of flow chemistry enable biosynthesis to overcome well-known limitations of "classic" enzymatic catalysis, such as time-consuming work-ups and enzyme inhibition, as well as difficult scale-up and process intensifications. Moreover, continuous flow biocatalysis provides access to practical, economical and more sustainable synthetic pathways, an important aspect for the future of pharmaceutical companies if they want to compete in the market while complying with European Medicines Agency (EMA), Food and Drug Administration (FDA) and green chemistry requirements. This review focuses on the most recent advances in the use of flow biocatalysis for the synthesis of active pharmaceutical ingredients (APIs), pharmaceuticals and natural products, and the advantages and limitations are discussed.

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

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.

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

Ebselen is the leader of selenorganic compounds, and starting from its identification as mimetic of the key antioxidant enzyme glutathione peroxidase, several papers have appeared in literature claiming its biological activities. It was the subject of several clinical trials and it is currently in clinical evaluation for the treatment of COVID-19 patients. Given our interest in the synthesis and pharmacological evaluation of selenorganic derivatives with this review, we aimed to collect all the papers focused on the biological evaluation of ebselen and its close analogues, covering the timeline between 2016 and most of 2021. Our analysis evidences that, even if it lacks specificity when tested in vitro, being able to bind to every reactive cysteine, it proved to be always well tolerated in vivo, exerting no sign of toxicity whatever the administered doses. Besides, looking at the literature, we realized that no review article dealing with the synthetic approaches for the construction of the benzo[d][1,2]-selenazol-3(2H)-one scaffold is available; thus, a section of the present review article is completely devoted to this specific topic.

l-Arginine Improves Solubility and ANTI SARS-CoV-2 Mpro Activity of Rutin but Not the Antiviral Activity in Cells.

The COVID-19 pandemic outbreak prompts an urgent need for efficient therapeutics, and repurposing of known drugs has been extensively used in an attempt to get to anti-SARS-CoV-2 agents in the shortest possible time. The glycoside rutin shows manifold pharmacological activities and, despite its use being limited by its poor solubility in water, it is the active principle of many pharmaceutical preparations. We herein report our in silico and experimental investigations of rutin as a SARS-CoV-2 Mpro inhibitor and of its water solubility improvement obtained by mixing it with l-arginine. Tests of the rutin/l-arginine mixture in a cellular model of SARS-CoV-2 infection highlighted that the mixture still suffers from unfavorable pharmacokinetic properties, but nonetheless, the results of this study suggest that rutin might be a good starting point for hit optimization.

Continuous Bioinspired Oxidation of Sulfides.

A simple, efficient, and selective oxidation under flow conditions of sulfides into their corresponding sulfoxides and sulfones is reported herein, using as a catalyst perselenic acid generated in situ by the oxidation of selenium (IV) oxide in a diluted aqueous solution of hydrogen peroxide as the final oxidant. The scope of the proposed methodology was investigated using aryl alkyl sulfides, aryl vinyl sulfides, and dialkyl sulfides as substrates, evidencing, in general, a good applicability. The scaled-up synthesis of (methylsulfonyl)benzene was also demonstrated, leading to its gram-scale preparation.

Diselenides and Benzisoselenazolones as Antiproliferative Agents and Glutathione-S-Transferase Inhibitors.

A series of variously functionalized selenium-containing compounds were purposely synthesized and evaluated against a panel of cancer cell lines. Most of the compounds showed an interesting cytotoxicity profile with compound 5 showing a potent activity on MCF7 cells. The ethyl amino derivative 5 acts synergistically with cis-platin and inhibits the GST enzyme with a potency that well correlates with the cytotoxicity observed in MCF7 cells. A computational analysis suggests a possible binding mode on the GST enzyme. As the main outcome of the present study, the ethyl amino derivative 5 emerged as a valid lead compound for further, future developments.

Atom Efficient Preparation of Zinc Selenates for the Synthesis of Selenol Esters under "On Water" Conditions.

We describe here an atom efficient procedure to prepare selenol esters in good to excellent yields by reacting [(PhSe)2Zn] or [(PhSe)2Zn]TMEDA with acyl chlorides under "on water" conditions. The method is applicable to a series of aromatic and aliphatic acyl chlorides and tolerates the presence of other functionalities in the starting material.

Green Hydroselenation of Aryl Alkynes: Divinyl Selenides as a Precursor of Resveratrol.

A simple and efficient protocol to prepare divinyl selenides has been developed by the regio- and stereoselective addition of sodium selenide species to aryl alkynes. The nucleophilic species was generates in situ, from the reaction of elemental selenium with NaBH4, utilizing PEG-400 as the solvent. Several divinyl selenides were obtained in moderate to excellent yields with selectivity for the (Z,Z)-isomer by a one-step procedure that was carried out at 60 °C in short reaction times. The methodology was extended to tellurium, giving the desired divinyl tellurides in good yields. Furthermore, the Fe-catalyzed cross-coupling reaction of bis(3,5-dimethoxystyryl) selenide 3f with (4-methoxyphenyl)magnesium bromide 5 afforded resveratrol trimethyl ether 6 in 57% yield.

Organic Diselenides: Versatile Reagents, Precursors, and Intriguing Biologically Active Compounds.

In this account, we describe how some organic diselenides were successfully used in the past as reagents for asymmetric stereoselective synthesis and more recently as precursors of catalysts and reagents applied in new green protocols. A biomimetic approach offered the possibility to perform oxidative reactions using hydrogen peroxide as oxidant and water as medium affording the desired products in excellent yields under mild conditions. The umpolung of the selenium atom gave novel nucleophilic reagents having a strongly accelerated reaction rate in on water conditions. Finally, the use of diselenides to exploit specific biological activities is described here as seminal examples of a promising field of research currently under investigation in our group.

Diphenyl diselenide derivatives inhibit microbial biofilm formation involved in wound infection.

BACKGROUND: Organoselenium compounds have antimicrobial activity against some bacteria and fungi; furthermore, the antioxidant activity of diselenides has been demonstrated. The aim of the present work was to examine the in vitro minimal inhibitory concentration of a panel of differently substituted diselenides and their effectiveness in inhibiting biofilm formation and dispersing preformed microbial biofilm of Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus pyogenes and Pseudomonas aeruginosa and the yeast Candida albicans, all involved in wound infections. Moreover, the cytotoxicity of the compounds was determined in human dermal fibroblast and keratinocytes. In closing, we tested their direct antioxidant activity. RESULTS: Diselenides showed different antimicrobial activity, depending on the microorganism. All diselenides demonstrated a good antibiofilm activity against S. aureus and S. epidermidis, the compounds camphor diselenide, bis[ethyl-N-(2'-selenobenzoyl) glycinate] and bis[2'-seleno-N-(1-methyl-2-phenylethyl) benzamide] were active against S. pyogenes and C. albicans biofilm while only diselenides 2,2'-diselenidyldibenzoic acid and bis[ethyl-N-(2'-selenobenzoyl) glycinate] were effective against P. aeruginosa. Moreover, the compounds bis[ethyl-N-(2'-selenobenzoyl) glycinate] and bis[2'-seleno-N-(1-methyl-2-phenylethyl) benzamide] showed an antioxidant activity at concentrations lower than the 50 % of cytotoxic concentration. CONCLUSIONS: Because microbial biofilms are implicated in chronic infection of wounds and treatment failure, the combination of antimicrobial activity and potential radical scavenging effects may contribute to the improvement of wound healing. Therefore, this study suggests that bis[ethylN-(2'-selenobenzoyl) glycinate] and bis[2'-seleno-N-(1-methyl-2-phenylethyl) benzamide] are promising compounds to be used in preventing and treating microbial wound infections.

Water and Aqueous Mixtures as Convenient Alternative Media for Organoselenium Chemistry.

Even if water is the natural environment for bioorganic reactions, its use in organic chemistry is often severely limited by the high insolubility of the organic derivatives. In this review, we introduce some examples of the use of water to perform organoselenium chemistry. We mainly discuss the advantages of this medium when the recyclability is demonstrated and when the water can control the selectivity of a reaction or enhance the reaction rate.

Selenium Catalyzed Oxidation of Aldehydes: Green Synthesis of Carboxylic Acids and Esters.

The stoichiometric use of hydrogen peroxide in the presence of a selenium-containing catalyst in water is here reported as a new ecofriendly protocol for the synthesis of variously functionalized carboxylic acids and esters. The method affords the desired products in good to excellent yields under very mild conditions starting directly from commercially available aldehydes. Using benzaldehyde as a prototype the gram scale synthesis of benzoic acid is described, in which the aqueous medium and the catalyst could be recycled at last five times while achieving an 87% overall yield.

Exploiting the anti-HIV 6-desfluoroquinolones to design multiple ligands.

It is getting clearer that many drugs effective in different therapeutic areas act on multiple rather than single targets. The application of polypharmacology concepts might have numerous advantages especially for disease such as HIV/AIDS, where the rapid emergence of resistance requires a complex combination of more than one drug. In this paper, we have designed three hybrid molecules combining WM5, a quinolone derivative we previously identified as HIV Tat-mediated transcription (TMT) inhibitor, with the tricyclic core of nevirapine and BILR 355BS (BILR) non-nucleoside reverse transcriptase inhibitors (NNRTIs) to investigate whether it could be possible to obtain molecules acting on both transcription steps of the HIV replicative cycle. One among the three designed multiple ligands, reached this goal. Indeed, compound 1 inhibited both TMT and reverse transcriptase (RT) activity. Unexpectedly, while the anti-TMT activity exerted by compound 1 resulted into a selective inhibition of HIV-1 reactivation from latently infected OM10.1 cells, the anti-RT properties shown by all of the synthesized compounds did not translate into an anti-HIV activity in acutely infected cells. Thus, we have herein produced the proof of concept that the design of dual TMT-RT inhibitors is indeed possible, but optimization efforts are needed to obtain more potent derivatives.