New insights in the mechanism of the SARS-CoV-2 M inhibition by benzisoselenazolones and diselenides.

Although global vaccination campaigns alleviated the SARS-CoV-2 pandemic in terms of morbidity and mortality, the ability of the virus to originate mutants may reduce the efficacy of vaccines, posing a serious risk of a renewed pandemic. There is therefore a need to develop small molecules capable of targeting conserved viral targets, such as the main protease (M). Here, a series of benzisoselenazolones and diselenides were tested for their ability to inhibit M; then the most potent compounds were measured for antiviral activity in vitro, and the mechanism of action was investigated.

Organic Selenium induces ferroptosis in pancreatic cancer cells.

Pancreatic ductal adenocarcinoma (PDA) cells reprogram both mitochondrial and lysosomal functions to support growth. At the same time, this causes significant dishomeostasis of free radicals. While this is compensated by the upregulation of detoxification mechanisms, it also represents a potential vulnerability.

Role of Group 12 Metals in the Reduction of HO 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.

In vitro toxicological assessment of PhSeZnCl in human liver cells.

Unlabelled: Phenylselenenylzinc chloride (PhSeZnCl) is an air-stable selenolate, easily synthesizable through oxidative insertion of elemental zinc into the Se-halogen bond of the commercially available phenylselenyl chloride. PhSeZnCl was shown to possess a marked GPx-like activity both in NMR and in vitro tests, and to effectively react with cellular thiols, and was supposed for a potential use in the chemotherapy of drug-resistant cancers. However, activity of PhSeZnCl in hepatic cells has never been tested before now.

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.

FDA-Approved Small Molecules in 2022: Clinical Uses and Their Synthesis.

This review describes the recently FDA-approved drugs (in the year 2022). Many of these products contain active moieties that FDA had not previously approved, either as a single ingredient or as part of a combination. These products frequently provide important new therapies for patients with multiple unmet diseases.

Chalcogenium-AZT Derivatives: A Plausible Strategy To Tackle The RT-Inhibitors-Related Oxidative Stress While Maintaining Their Anti- HIV Properties.

Background: This study presents the synthesis and multi-target behavior of the new 5'-hydroxy-3-(chalcogenyl-triazoyl)-thymidine and the biological evaluation of these compounds as antioxidant and anti-HIV agents.

Objective: Antiretroviral therapy induces oxidative stress. Based on this, this manuscript's main objective is to prepare compounds that combine anti-HIV and antioxidant activities.

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.

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 () or prednisone acetate () 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.

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.

"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.

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.

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.

Seleno-Functionalization of Quercetin Improves the Non-Covalent Inhibition of M 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 (M) is among the most promising molecular targets in light of its importance during the viral replication cycle. The natural flavonoid quercetin has been recently reported to be a potent M inhibitor in vitro, and we explored the effect produced by the introduction of organoselenium functionalities in this scaffold.

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.

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.

Sweet Selenium: Synthesis and Properties of Selenium-Containing Sugars and Derivatives.

In the last decades, organoselenium compounds gained interest due to their important biological features. However, the lack of solubility, which characterizes most of them, makes their actual clinical exploitability a hard to reach goal. Selenosugars, with their intrinsic polarity, do not suffer from this issue and as a result, they can be conceived as a useful alternative.

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.

The nature of G⋯E-Y σ(3c-4e) in -Me GCHCHEY (Me G = MeN and MeE; E = O, S, Se and Te; Y = F, Cl, Br, EMe and Me) with contributions from CT and compliance constants in noncovalent G⋯E interactions.

The intrinsic dynamic and static nature of G-*-E-*-Y σ(3c-4e) interactions was elucidated with the quantum theory of atoms in molecules dual functional analysis (QTAIM-DFA), employing -Me GCHCHEY (Me G = MeN and MeE; E = O, S, Se and Te; Y = F, Cl, Br, I, EMe and Me). Asterisks (*) are employed to emphasize the existence of bond critical points (BCPs) on the bond paths (BPs), corresponding to the interactions in question. Data from the fully optimized structure correspond to the static nature of interactions.

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 showing a potent activity on MCF7 cells. The ethyl amino derivative acts synergistically with -platin and inhibits the GST enzyme with a potency that well correlates with the cytotoxicity observed in MCF7 cells.

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.

2-Phenylquinazolinones as dual-activity tankyrase-kinase inhibitors.

Tankyrases (TNKSs) are enzymes specialized in catalyzing poly-ADP-ribosylation of target proteins. Several studies have validated TNKSs as anti-cancer drug targets due to their regulatory role in Wnt/β-catenin pathway. Recently a lot of effort has been put into developing more potent and selective TNKS inhibitors and optimizing them towards anti-cancer agents.

NCp7: targeting a multitask protein for next-generation anti-HIV drug development part 2. Noncovalent inhibitors and nucleic acid binders.

Nucleocapsid protein 7 (NCp7) represents a viable target not yet reached by the currently available antiretrovirals. It is a small and highly basic protein, which is essential for multiple stages of the viral replicative cycle, with its structure preserved in all viral strains, including clinical isolates. NCp7 can be inhibited covalently, noncovalently and by shielding the nucleic acid (NA) substrates of its chaperone activity.

NCp7: targeting a multitasking protein for next-generation anti-HIV drug development part 1: covalent inhibitors.

The major internal component of the HIV virion core is the nucleocapsid protein 7 (NCp7), a small, highly basic protein that is essential for multiple stages of the viral replicative cycle, and whose structure is preserved in all viral strains, including clinical isolates from therapy-experienced patients. This key protein is recognised as a potential target for an effective next-generation antiretroviral therapy, because it could offer the possibility to develop broad-spectrum agents that are less prone to select for resistant strains. Here, we provide a comprehensive overview of the covalent NCp7 inhibitors that have emerged over the past 25 years of drug discovery campaigns, emphasising, where possible, their structure-activity relationships (SARs) and pharmacophoric features.