Visible-Light-Triggered Synthesis of N-α-Ketoacylated Sulfoximines by Denitrogenative and Oxidative Functionalization of Vinyl Azides.

We have introduced a sulfoximidation reaction initiated by visible light between α-phenyl vinyl azides and NH-sulfoximines. The cost-effective and readily accessible hypervalent iodine reagent (PIDA) easily promoted the oxidative sulfoximidation process to afford N-α-ketoacylated sulfoximines in good to high yields, involving the formation of two new C-O bonds and one C-N bond. Additionally, the protocol offers noteworthy advantages, including its metal-free and photocatalyst-free reaction and its broad substrate compatibility.

Visible-Light-Promoted Metal- and Photocatalyst-Free Reactions between Arylglyoxylic Acids and Tetraalkylthiuram Disulfides: Synthesis of α-Ketoamides.

A convenient and new synthetic approach has been developed for the oxidative cross-coupling of the C-N bond through the reaction between arylglyoxylic acids and tetraalkylthiuram disulfides. The reaction proceeds under ambient air at room temperature in the presence of visible light. This reaction offers a metal-, base-, photocatalyst-, and solvent-free synthesis of various α-ketoamides with moderate to excellent yields via the radical pathway. In addition, this protocol demonstrates the potential application of a gram-scale synthesis.

One-pot Synthesis and Photophysical Studies of Α-cycloamino-substituted 5-aryl-2,2'-bipyridines.

A series of α-cycloamine substituted 2,2'-bipyridines 3ae'-3ce' was obtained via the one-pot approach based on ipso-substitution of a cyano-group in 1,2,4-triazines, followed by aza-Diels-Alder reaction in good yields. Photophysical properties, including fluorosolvatochromism, were studied for 3ae'-3ce' and were compared with α-unsubstituted 2,2'-bipyridines. In addition, dipole moments differences in ground and excited states were calculated by both Lippert-Mataga equation and DFT studies and were compared to each other. The correlation between the size of cycloamine unit and the dipole moments differences value (based on Lippert-Mataga equation) was observed. In addition charge transfer indices (DCT, Λ, H and t) were calculated to demonstrate influence of molecular structure on the intramolecular charge transfer degree.

New Fluorescent Dye for the Detection of Zn2+ in Living Cells and Fixed Sections of the Rat Pancreas.

We report the synthesis and characterization of a new 4-methoxyphenyl-2,2'-bipyridine-based ligand, such as 12, bearing dipicolylaminomethyl core as a receptor unit, as a probe for the fluorescence "turn-on" detection of Zn2+. Thus, in the presence of Zn2+ the probe 12 exhibited a fluorescence enhancement with a Stokes shift of ~ 180 nm and photoluminescence quantum yields value of ~ 1.0. In addition, 12 exhibited higher binding constant for Zn2+ (~ 2 × 105 M-1) with the LOD reaching the nanomolar level (~ 0.1 × 10-9 M) compare to the previously reported probe 1. The stoichiometry and structure of the [Zn(12)]2+ and [Zn(1)]2+ complexes were supported by XRD analysis, DFT calculations and 1H NMR experiments. It was postulated that, as a result of binding of Zn2+, the sample exhibited a bright "on" state via the PET-ICT processes. Molecular docking studies and confocal fluorescence microscopy experiments demonstrated that the probe 12 could be used for the fluorescence detection of Zn2+ not only in artificially enriched with zinc salts live cells, but also in fixed tissues with cations are in a bound state. The high binding constant of compound 12 to Zn2+ cation allows it to be used for the accurate localization of pancreatic beta cells (islets of Langerhans).

Recent Trends in the Antidiabetic Prominence of Natural and Synthetic Analogues of Aurones.

Natural products are a boundless source for the development of pharmaceutical agents against a wide range of human diseases. Accordingly, naturally occurring aurones possess various biological benefits, such as anticancer, antioxidant, antimicrobial, antidiabetic, anti-inflammatory, antiviral and neuroprotective effects. In addition, various studies have revealed that aurones are potential templates for the regulation of diabetes mellitus and its associated complications. Likewise, certain aurones and their analogues have been found to be remarkable kinase inhibitors of DARK2, PPAR-γ, PTPM1, AGE, α-amylase and α-glucosidase, which represents a promising approach for the treatment of chronic metabolic disorders such as diabetes. Therefore, in our present study, we provide a detailed account of the advances in aurones as antidiabetic agents over the past decade.

Exploration of NMI-MsCl mediated amide bond formation for the synthesis of novel 3,5-substituted-1,2,4-oxadiazole derivatives: synthesis, evaluation of anti-inflammatory activity and molecular docking studies.

We herein report the facile synthesis of a series of 3,5-substituted-1,2,4-oxadiazole derivatives 9a-e and 10a-e in good to excellent yields by employing NMI-MsCl mediated amide bond formation reaction. The anti-inflammatory potential of the newly synthesized compounds were evaluated by anti-denaturation assay using diclofenac sodium as the reference drug. The compounds 9a and 9d demonstrated promising activity profile when compared to the reference standard. The SAR and molecular docking studies were also carried out for obtaining more details about the profound activity profile of the synthesized molecules. The synthesized compounds were docked against two target proteins TGF-ß and IL-1 by AutoDock vina and Auto Dock 4.2.

Pillararenes as Promising Carriers for Drug Delivery.

Since their discovery in 2008 by N. Ogoshi and co-authors, pillararenes (PAs) have become popular hosts for molecular recognition and supramolecular chemistry, as well as other practical applications. The most useful property of these fascinating macrocycles is their ability to accommodate reversibly guest molecules of various kinds, including drugs or drug-like molecules, in their highly ordered rigid cavity. The last two features of pillararenes are widely used in various pillararene-based molecular devices and machines, stimuli-responsive supramolecular/host-guest systems, porous/nonporous materials, organic-inorganic hybrid systems, catalysis, and, finally, drug delivery systems. In this review, the most representative and important results on using pillararenes for drug delivery systems for the last decade are presented.

Plant Coumarins with Anti-HIV Activity: Isolation and Mechanisms of Action.

This review summarizes and systematizes the literature on the anti-HIV activity of plant coumarins with emphasis on isolation and the mechanism of their antiviral action. This review summarizes the information on the anti-HIV properties of simple coumarins as well as annulated furano- and pyranocoumarins and shows that coumarins of plant origin can act by several mechanisms: inhibition of HIV reverse transcriptase and integrase, inhibition of cellular factors that regulate HIV-1 replication, and transmission of viral particles from infected macrophages to healthy ones. It is important to note that some pyranocoumarins are able to act through several mechanisms or bind to several sites, which ensures the resistance of these compounds to HIV mutations. Here we review the last two decades of research on the anti-HIV activity of naturally occurring coumarins.

Polyaromatic Hydrocarbon (PAH)-Based Aza-POPOPs: Synthesis, Photophysical Studies, and Nitroanalyte Sensing Abilities.

1,4-Bis(5-phenyl-2-oxazolyl)benzene (POPOP) is a common scintillation fluorescent laser dye. In this manuscript, the synthesis of 2-Ar-5-(4-(4-Ar'-1H-1,2,3-triazol-1-yl)phenyl)-1,3,4-oxadiazoles (Ar, Ar' = Ph, naphtalenyl-2, pyrenyl-1, triphenilenyl-2), as PAH-based aza-analogues of POPOP, by means of Cu-catalyzed click reaction between 2-(4-azidophenyl)-5-Ar-1,3,4-oxadiazole and terminal ethynyl-substituted PAHs is reported. An investigation of the photophysical properties of the obtained products was carried out, and their sensory response to nitroanalytes was evaluated. In the case of pyrenyl-1-substituted aza-POPOP, dramatic fluorescence quenching by nitroanalytes was observed.

Comparison of Photophysical Properties of Lanthanide(III) Complexes of DTTA- or DO3A-Appended Aryl-2,2'-Bipyridines.

New Tb(III) and Eu(III) complexes based on aryl-2,2'-bipyridine ligands with a cyclic DO3A chelating unit appended in the alpha position of the bipyridine core were synthesized. The photophysical properties of these complexes were compared with those of complexes of ligands with identical aryl-2,2'-bipyridine chromophores, but with an acyclic DTTA residue as an additional chelating site in the alpha position of the bipyridine core. The nature of the polyaminocarboxylic acid fragments was found to have a significant influence on the luminescence. For some of the Eu(III) complexes, upon the transition from acyclic DTTA- to the cyclic DO3A-appended ligands, a noticeable increase in the intensity of Eu(III) luminescence was observed, with an increase in the quantum yield of up to 2.55 times. In contrast, for most of the Tb(III) complexes, a similar transition resulted in a noticeable decrease in the luminescence intensity of the Tb(III) cation.

New Degradable Semiconducting Polymers for Photoacoustic Imaging of λ-Carrageenan-Induced Arthritis Mouse Model.

Semiconducting polymer has a high extinction coefficient and a long band absorption and can be used as a photoacoustic imaging contrast agent. However, nonbiodegradable semiconducting polymers may cause biosafety issues due to being retained in the body. Therefore, developing degradable semiconducting polymers is necessary for in vivo imaging. Herein, we developed three degradable semiconducting polymers with unique optical properties. We adjusted the optical properties of semiconducting polymers by designing the molecular structure of semiconducting polymers. Polymers with a donor-π-acceptor structure could easily improve the optical properties through adjusting the donor or acceptor units. Through adjusting the electron-donor and -acceptor units, three diketopyrrolopyrrole derivative polymers (DPPTz, DPPQu, and DPPWu) were synthesized and converted into nanosize particles. By introducing the degradable chemical groups in the main chain structure of semiconducting polymers, diketopyrrolopyrrole polymers could be degraded by ClO-. Among these nanosize particles, DPPTz NPs and DPPQu NPs were used to achieve the in vivo photoacoustic imaging of λ-carrageenan-induced arthritis mouse model. This work provides a novel design idea for the designing of red-shifted semiconducting polymer with degradable properties.

Brønsted acidic ionic liquid-catalyzed tandem reaction: an efficient and sustainable approach towards the regioselective synthesis and molecular docking studies of 4-hydroxycoumarin-substituted indoles bearing lower E-factors.

1-Butane sulfonic acid-3-methylimidazolium tosylate, [BSMIM]OTs, is a remarkable catalyst for the cascade synthesis of coumarin-functionalized indole derivatives via a tandem cyclization reaction of aniline and phenylglyoxal monohydrate. This reaction possibly proceeds through imine formation/nucleophilic addition/cyclization. In addition, this method shows lower E-factors. A clean reaction, easily accessible reactants, metal-free and environmentally friendly reaction conditions, and reusability of the catalyst are the notable advantages of this procedure. In addition, molecular docking studies show the theoretical possibility of binding these types of synthesized compounds to key proteins in tumorigenesis.

Synthetic approaches to 1,2,4-triazolo[5,1-c][1,2,4]triazin-7-ones as basic heterocyclic structures of the antiviral drug Riamilovir ("Triazavirin®") active against SARS-CoV-2 (COVID-19).

Fragments of 1,2,4-triazolo[5,1-c][1,2,4]triazin-7-one are found in many compounds with various types of biological activities, including the antiviral drug Riamilovir (Triazavirin®), which shows activity against SARS-CoV-2 (COVID-19). Therefore, the development of convenient methods for the synthesis of new derivatives of 1,2,4-triazolo[5,1-c][1,2,4]triazin-7-one is always in demand. This review systematizes the information on the most common synthetic methods for constructing the 1,2,4-triazolo[5,1-c][1,2,4]triazin-7-one heterocyclic system.

Asymmetrically Functionalized 1,3-Di(2-pyridyl)benzenes: Synthesis and Photophysical Studies.

A convenient synthetic approach to asymmetrically functionalized 1,3-di(2-pyridyl)benzenes starting from 3-(3-bromophenyl)-1,2,4-triazines using sequential aza-Diels-Alder reactions and Stille cross-coupling is reported. Photophysical properties of the obtained compounds are studied.

Ethyl-4-(aryl)-6-methyl-2-(oxo/thio)-3,4-dihydro-1H-pyrimidine-5-carboxylates: Silica supported bismuth(III)triflate catalyzed synthesis and antioxidant activity.

Novel ethyl-4-(aryl)-6-methyl-2-(oxo/thio)-3,4-dihydro-1H-pyrimidine-5-carboxylates were synthesized from one-pot, three-component Biginelli reaction of aryl aldehydes, ethyl acetoacetate and urea/ thiourea by catalytic action of silica supported Bismuth(III) triflate, a Lewis acid. All the synthesized compounds were structurally characterized by spectral (IR, 1H NMR & 13C NMR spectroscopic and Mass spectrometric) and elemental (C, H & N) analyses. The present protocol has deserved novel as, formed the products in high yields with short reaction times, involved eco-friendly methodology and reusable heterogeneous Lewis acid catalyst. The title compounds were screened for in vitro DPPH free radical scavenging antioxidant activity and identified 4i, 4j, 4h & 4f as potential antioxidants. The obtained in vitro results were correlated with molecular docking, ADMET, QSAR, Bioactivity & toxicity risk studies and molecular finger print properties and found that in silico binding affinities were identified in good correlation with in vitro antioxidant activity and studied the structure activity relationship. The molecular docking study has disclosed strong hydrogen bonding interactions of title compounds with aspartic acid (ASP197) aminoacid residue of 2HCK, a complex enzyme of haematopoietic cell kinase and quercetin. Results of toxicology study evaluated for potential risks of compounds have revealed title compounds as safer drugs. In ultimate the study has established ligand's antioxidant potentiality as they effectively binds with ASP197 amino acid of Chain A hence confirms the inhibition of growth of reactive oxygen species in vivo. In addition, the title compounds have been identified as potential blood-brain barrier penetrable entities and efficient central nervous system (CNS) active neuro-protective antioxidant agents.

Synthesis and biological evaluation of novel dialkyl (4-amino-5H-chromeno[2,3-d]pyrimidin-5-yl)phosphonates.

This study reports the design and synthesis of novel dialkyl (4-amino-5H-chromeno[2,3-d]pyrimidin-5-yl)phosphonates as potential antitumor agents against A549 (lung cancer), DU-145 (prostate cancer), PC-3 (prostate cancer), HeLa (cervical cancer) and MCF-7 (breast cancer), cell lines evidenced from the in vitro antitumor studies performed by MTT assay (across 10-30 µM concentrations). The structural eminence of these synthesized molecules has emanated by designing the structural core by uniting the chromene, pyrimidine and phosphonate moieties into one, which has augmented their novelty and made them unreported. Further the deep structural activity relationship study investigations articulated that the title compounds are promising drug-like compounds and potential inhibitor of histidine amino acid residue present on the respective enzymatic proteins [3QJZ (A549), 3VHE (DU-145), 3V49 (PC-3), 3F81 (HeLa), & 3R7Q (MCF-7)] of the cell lines screened and are identified as responsible for the multi-faceted antitumor activities predicted in vitro. The obtained results were further supported by molecular docking studies, QSAR, ADMET, and bioactivity studies which have supported them as potential BBB penetrable molecules and proficient CNS active neuro-protective agents during drug delivery.

In Silico Evaluation of Antifungal Compounds from Marine Sponges against COVID-19-Associated Mucormycosis.

The world is already facing the devastating effects of the SARS-CoV-2 pandemic. A disseminated mucormycosis epidemic emerged to worsen this situation, causing havoc, especially in India. This research aimed to perform a multitargeted docking study of marine-sponge-origin bioactive compounds against mucormycosis. Information on proven drug targets and marine sponge compounds was obtained via a literature search. A total of seven different targets were selected. Thirty-five compounds were chosen using the PASS online program. For homology modeling and molecular docking, FASTA sequences and 3D structures for protein targets were retrieved from NCBI and PDB databases. Autodock Vina in PyRx 0.8 was used for docking studies. Further, molecular dynamics simulations were performed using the IMODS server for top-ranked docked complexes. Moreover, the drug-like properties and toxicity analyses were performed using Lipinski parameters in Swiss-ADME, OSIRIS, ProTox-II, pkCSM, and StopTox servers. The results indicated that naamine D, latrunculin A and S, (+)-curcudiol, (+)-curcuphenol, aurantoside I, and hyrtimomine A had the highest binding affinity values of -8.8, -8.6, -9.8, -11.4, -8.0, -11.4, and -9.0 kcal/mol, respectively. In sum, all MNPs included in this study are good candidates against mucormycosis. (+)-curcudiol and (+)-curcuphenol are promising compounds due to their broad-spectrum target inhibition potential.

Folic Acid Antimetabolites (Antifolates): A Brief Review on Synthetic Strategies and Application Opportunities.

Antimetabolites of folic acid represent a large group of drugs and drug candidates, including those for cancer chemotherapy. In this current review, the most common methods and approaches are presented for the synthesis of therapeutically significant antimetabolites of folic acid, which are Methotrexate (MTX), Raltitrexed (Tomudex, ZD1694), Pralatrexate, Pemetrexed, TNP-351, and Lometrexol. In addition, the applications or uses of these folic acid antimetabolites are also discussed.

Synthesis and Photophysical Properties of α-(N-Biphenyl)-Substituted 2,2'-Bipyridine-Based Push-Pull Fluorophores.

A series of new α-(N-biphenyl)-substituted 2,2'-bipyridines were obtained through the combination of the ipso-nucleophilic aromatic substitution of the C5-cyano group, aza-Diels-Alder and Suzuki cross-coupling reactions, starting from 5-cyano-1,2,4-triazines. For the obtained compounds, photophysical and fluorosolvatochromic properties were studied. Fluorophores 3l and 3b demonstrated unexpected AIEE activity, while 3a and 3h showed promising nitroexplosive detection abilities.

Mechanochemical Approach towards Multi-Functionalized 1,2,3-Triazoles and Anti-Seizure Drug Rufinamide Analogs Using Copper Beads.

Highly regiospecific, copper-salt-free and neat conditions have been demonstrated for the 1,3-dipolar azide-alkyne cycloaddition (AAC) reactions under mechanochemical conditions. A group of structurally challenging alkynes and heterocyclic derivatives was efficiently implemented to achieve highly functionalized 1,4-disubstituted-1,2,3-triazoles in good to excellent yield by using the Cu beads without generation of unwanted byproducts. Furthermore, the high-speed ball milling (HSBM) strategy has also been extended to the synthesis of the commercially available pharmaceutical agent, Rufinamide, an antiepileptic drug (AED) and its analogues. The same strategy was also applied for the synthesis of the Cl-derivative of Rufinamide. Analysis of the single crystal XRD data of the triazole was also performed for the final structural confirmation. The Cu beads are easily recoverable from the reaction mixture and used for the further reactions without any special treatment.