Kavirayani Indira Priyadarsini

Selenium-centered radicals stabilized by 2c-3e hemi-bonds are vital in organic synthesis and redox biology. This review unifies fragmented literature, bridging their generation, detection, and chemical reactivity with their role in ROS scavenging.

The past two decades of this century have faced half a dozen pandemics caused by different kinds of viruses, affecting millions of people globally. Among them three zoonotic viruses of the beta-coronavirus family, namely SARS-CoV-1, MERS-CoV and SARS-CoV-2, have emerged in a span of 17 years. Prevention of viral infection using vaccines is the foremost strategy to combat viral infection, but development of a vaccine for a virus remains a challenging task due to high genetic diversity and high mutation rates. Treatment of viral disease at different stages by antiviral drugs is another strategy. Several antiviral agents, primarily aiming to disrupt the viral life cycle, have been developed. Extensive research in different labs across the globe has shown that selenium deficiency has been associated with pathogenicity of several viruses like influenza viruses, HIV, HBV, HSV-1, etc. While dietary selenium supplementation has been practiced clinically, researchers are now focusing on developing new synthetic organoselenium compounds as novel antiviral agents. In this essay we have covered different classes of selenium compounds, viz. N-heterocyclic selenium derivatives, ebselen and its derivatives, organoselenium compounds, and selenium nanoparticles, which have been evaluated for effective management of viral infections.

3,3′-Diselenodipropionic acid (DSePA) is a water-soluble deaminated analogue of selenocystine. Owing to its acidic groups and the redox activity of the diselenide moiety present in it, DSePA was found to serve as an efficacious catalyst in the synthesis of tetrahydrobenzo[b]pyran derivatives through a three-component one-pot condensation reaction under ultrasonic conditions in an aqueous ethanol mixture. A comparative study was conducted to assess the catalytic performance of DSePA and its non-selenium analogue in synthesizing tetrahydrobenzo[b]pyran derivatives. It was observed that reactions catalyzed by DSePA exhibited high yields, ranging from 80 to 95%. The established synthetic protocol was compatible with a diverse array of aromatic aldehydes bearing electron-donating or electron-withdrawing groups, resulting in excellent yields within short reaction times (10–25 minutes). Notable features of this synthetic approach include operational simplicity, the use of an environmentally benign catalyst, mild reaction conditions, high product yields, and expeditious reaction times.

Aim of the study The rising instances of multidrug-resistant pathogens are rapidly evolving into a global healthcare crisis. Identifying new ways of synthesis of antibiotics is both time-consuming and expensive. Repurposing existing drugs for the treatment of such antimicrobial-resistant pathogens has also been explored. Methods and results In the current study, ebselen was screened for antibacterial and antibiofilm activity against Serratia marcescens. Various antibacterial studies such as minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), time-kill curves, intracellular reactive oxygen species (ROS) quantification, and colony-forming unit assays were performed. The antibiofilm potential was assayed by biofilm inhibition, cell surface hydrophobicity assay, eradication, quantification of extracellular DNA (eDNA), and extracellular polymeric substance (EPS) layer and scanning electron microscopy (SEM) analysis were performed. Anti-quorum sensing assay was validated by quantifying the virulence factors production. Further molecular docking of ebselen with two quorum sensing (QS) specific proteins was also carried out. Antibacterial susceptibility tests showed potent antimicrobial activity of ebselen against S. marcescens with MIC₅₀ of 14 μg/mL. Ebselen’s ability to disturb the redox environment by inducing significant ROS generation led to bacterial death. It also showed concentration-dependent bactericidal activity as indicated by reduced bacterial growth and colony-forming unit propagation. Ebselen was also found to prevent biofilm attachment by altering the cell surface hydrophobicity while also being effective against preformed biofilms as validated by scanning electron microscopy (SEM) analysis. Additionally, ebselen showed reduced virulence factors like urease enzyme activity and prodigiosin pigment production indicating its promising anti-quorum sensing potential. Molecular docking analysis validated the strong binding of ebselen with QS-specific proteins (1Joe and PigG) with binding energies of − 6.6 and − 8.1kj/mol through hydrogen bonds and aromatic interactions. These results show that ebselen has potent antibiofilm potential that can be explored to identify treatment against bacterial infections.

Diselenodipropionic acid (DSePA), a selenocystine derivative, has emerged as a promising pharmacologically active organoselenium compound. In order to fully utilize its activity, there is a need to understand its transport mechanism as well as interaction with circulatory proteins like human serum albumin (HSA). Accordingly, interaction between DSePA and HSA has been investigated in this study by employing integrated spectroscopic and docking methods. Both absorption and fluorescence spectra of HSA showed significant changes on addition of DSePA. From these changes the binding constant (K_b) has been estimated to be (2.5 ± 0.1) × 10⁵ M⁻¹ and (3.2 ± 0.3) × 10⁵ M⁻¹, respectively by employing Benessi-Hildebrand and modified Stern-Volmer equations. The molecular interaction was also corroborated by isothermal titration calorimetry (ITC) with mono-model fitting, from which binding constant (K_b) value was also estimated. The HSA-DSePA complex was analyzed by small angle X-ray scattering and circular dichroism techniques. Molecular docking studies suggested that DSePA binds at domain IIA with specific molecular interactions at Trp214, Lys199, Arg222, Ala291, Leu238, Arg257 amino acid residues. These results provide evidence for the interaction between DSePA and HSA and similar tools can be extrapolated to understand interaction with many other proteins during its metabolic process.

Compounds based on two different elements, selenium and platinum, have been attracting researchers to deploy them in chemotherapy of human cancers. Selenium, as a micronutrient plays many important roles in human biology. Different research groups have been developing both inorganic and organoselenium compounds for potential use for treatment of diseases including cancer. New synthetic designs are emerging to develop selenium compounds either as chemo-preventive or chemotherapeutic agents. Platinum is another important element in cancer therapy. Platinum-based drugs are the first line of treatment for many cancers. Attracted by the fact that chalcogens are excellent ligands for platinum, new ideas are emerging to develop selenium-bound platinum compounds as cancer therapeutics. In this direction, our group has made a beginning to develop stable seleno-platinum compounds to explore their anti-cancer potentials.

One of the important features influencing the biological applications of organoselenium compounds is their redox state, which in turn is affected by their interactions with nearby heteroatoms. To modulate the biological action of selenium in such compounds, researchers have designed new structural motifs and also developed new formulations using inorganic nanoparticles. Metal nanoparticles such as gold nanoparticles (GNPs) and magnetic nanoparticles (MNPs) like iron oxide (Fe₃O₄) have been extensively studied for conjugation with many heteroatoms (sulphur, nitrogen and oxygen) containing ligands. Selenium, being more polarisable than sulphur, can induce significant surface passivation, thereby providing easy modulations with physico-chemical properties. Considering this, we investigated the physico-chemical properties of a few selenium compounds conjugated to GNPs and MNPs. The GNP conjugates were characterised by spectroscopic and microscopic tools, such as optical absorption, Raman spectroscopy, dynamic light scattering (DLS), the zeta potential and transmission electron microscopy (TEM). The results confirmed that the selenium atom was covalently conjugated to GNPs and this conjugation not only increased their electron transfer ability, but also their antioxidant ability. In another study, asymmetric phenyl selenides were conjugated with MNPs and characterised byX-ray diffraction (XRD), TEM, DLS and zeta potential. The radical scavenging ability of the selenium compounds improved upon conjugation with the MNPs. Therefore, the above studies confirmed that the redox activities of selenium compounds can be modulated upon conjugation with inorganic nanoparticles, such as GNPs and MNPs, which in turn provides new avenues for delivering organoselenium compounds.

Over the years, organodiselenides have emerged as the biologically relevant class of molecules. On the one hand, such compounds are known for pro-oxidant effects leading to toxicity in biological systems. On the other hand, there are growing evidences about their bio-mimetic activities as catalysts such as glutathione peroxidase (GPx)-like activity. Our recent work has explored this paradoxical behavior of diselenides in developing antioxidants and/or anticancer agents. For this purpose, a number of alkyl and aryl diselenides have been evaluated in different biological models. The results have shown that aryl diselenides, in particular pyridinediselenides, altered the ratio of the intracellular thiol redox pairs of glutathione (GSH) and glutathione disulfide (GSSG) towards reduction (antioxidant) rather than oxidation (pro-oxidant) to protect normal cells against radiation damage and to induce cytotoxicity in tumor cells. Further, these studies have also postulated that the intracellular redox state, the level of thioredoxin reductase (TrxR), and reductive intermediates (e.g., selenol and/or selone) might play a very important role in the manifestation of the toxicities of aryl diselenides in cells.