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The Bucherer–Bergs multicomponent synthesis of hydantoins has been meticulously examined using density functional theory (DFT) at the B3LYP/6-311G level to scrutinise the reaction mechanism in diethyl ether as a solvent. This study explores all plausible pathways, optimises the structures of intermediates, and identifies corresponding transition states. Furthermore, a comprehensive computational analysis of molecular structures and their energy-structural correlations has been conducted. [ABSTRACT FROM AUTHOR]

Hydantoins, a class of five-membered heterocyclic compounds, exhibit diverse biological activities. The aim of this study was to synthesize and characterize a series of novel 3,5-disubstituted hydantoins and to investigate their antiproliferative activity against human cancer cell lines. The new hydantoin derivatives 5a–i were prepared as racemic mixtures of syn- and anti-isomers via a base-assisted intramolecular amidolysis of C-3 functionalized β-lactams. The enantiomers of syn-5a and anti-hydantoins 5b were separated by preparative high-performance liquid chromatography (HPLC) using n-hexane/2-propanol (90/10, v/v) as the mobile phase. The absolute configuration of the four allyl hydantoin enantiomers 5a was assigned based on a comparison of the experimental electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectra with those calculated using density functional theory (DFT). The antiproliferative activity evaluated in vitro against three different human cancer cell lines: HepG2 (liver hepatocellular carcinoma), A2780 (ovarian carcinoma), and MCF7 (breast adenocarcinoma), and on the non-tumor cell line HFF1 (normal human foreskin fibroblasts) using the MTT cell proliferation assay. In silico drug-like properties and ADMET profiles were estimated using the ADMET Predictor ver. 9.5 and the online server admetSAR. Eighteen new 3,5-disubstituted hydantoins were synthesized and characterized. The compound anti-5c showed potent cytotoxic activity against the human tumor cell line MCF7 (IC50 = 4.5 µmol/L) and the non-tumor cell line HFF1 (IC50 = 12.0 µmol/L). In silico analyzes revealed that the compounds exhibited moderate water solubility and membrane permeability and are likely substrates for CYP3A4 and P-glycoprotein and have a high probability of antiarthritic activity. [ABSTRACT FROM AUTHOR]

Five- and six-membered cyclic amide structures with an embedded endocyclic α-aza group (α-aza-lactams) not only represent masked or protected forms of α-amino acids, but also form the core of other medicinally relevant compound families such as (thio)hydantoins and di(tri)ketopiperazines. In recent years, catalytic methods have been discovered to synthesize these molecular scaffolds, particularly those bearing an α-stereogenic tri- or tetrasubstituted carbon center, enantioselectively. The wide variety of methods and catalytic activation strategies that have been successfully applied to this end in a short period of years is notable. This short review covers the most significant, highlighting their differences and complementarities. The methods are organized according to the disconnection approach to the target α-aza-lactam structure, which in most cases is deeply bound to the type of catalysis applied. 1 Introduction 2 Catalyst-Controlled Cα –H Functionalization (Approach a) 3 Decarboxylative α-AAA Reactions (Approach b) 4 Cα –X Substitution Reactions (Approach c) 5 De Novo Synthesis from Acyclic Precursors (Approach d) 6 Hydrogenation of (Addition to) α-Alkyliden-α-aza-lactams (Approach e) 7 Kinetic Resolution and Deracemization (Approach f) 8 Conclusions [ABSTRACT FROM AUTHOR]

In the light of recent progress in the development of SARS-CoV-2 main protease inhibitors, the synthesis of their key fragment, heterocyclic amino acids, is of great interest. Here, we report a method for the preparation of two new quisqualic acid analogs containing hydantoin and imidazolidinone moieties. The hydantoin analog was obtained using an amide ester cyclization, while the imidazolidinone unit was constructed by reductive amination and subsequent cyclization of a substituted ethylenediamine with carbonyldiimidazole. The presented approach provides the convergent synthesis of target analogs in 8 and 5 steps respectively. [ABSTRACT FROM AUTHOR]

Oncologists use molecular prediction/pharmacogenomics to improve Rx of cancer. Voltaire now wrong. [ABSTRACT FROM AUTHOR]

In the title molecule, C21H17N3O2, the five-membered ring is slightly ruffled and dihedral angles between the pendant six-membered rings and the central, five-membered ring vary between 50.78 (4) and 86.78 (10)°. The exocyclic nitrogen lone pair is involved in conjugated π bonding to the five-membered ring. In the crystal, a layered structure is generated by O—H...N and N—H...O hydrogen bonds plus C—H...π(ring) and weak π-stacking interactions.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase which plays a center role in the phosphorylation of a wide variety of proteins, generally leading to their inactivation. As such, GSK-3 is viewed as a therapeutic target. An ever-increasing number of small organic molecule inhibitors of GSK-3 have been reported. Phenylmethylene hydantoins are known to exhibit a wide range of inhibitory activities including for GSK-3β. A family of fourteen 2-heterocycle substituted methylene hydantoins (14, 17–29) were prepared and evaluated for the inhibition of GSK-3β at 25 μM. The IC50 values of five of these compounds was determined; the two best inhibitors are 5-[(4′-chloro-2-pyridinyl)methylene]hydantoin (IC50 = 2.14 ± 0.18 μM) and 5-[(6′-bromo-2-pyridinyl)methylene]hydantoin (IC50 = 3.39 ± 0.16 μM). The computational docking of the compounds with GSK-3β (pdb 1q41) revealed poses with hydrogen bonding to the backbone at Val135. The 5-[(heteroaryl)methylene]hydantoins did not strongly inhibit other metalloenzymes, demonstrating poor inhibitory activity against matrix metalloproteinase-12 at 25 μM and against human carbonic anhydrase at 200 μM, and were not inhibitors for Staphylococcus aureus pyruvate carboxylase at concentrations >1000 μM. [ABSTRACT FROM AUTHOR]

Hydantoin derivatives are versatile structural motifs found in natural products and various compounds with different biological or other properties. Due to their importance in both organic and medicinal chemistry, a number of synthetic procedures have been developed. In this article, a novel methodology utilizing N-Boc protected amino acid amides for their preparation has been described. The cyclisation process was accomplished using solid supported PPh3 and CBr4 as reagents affording substituted hydantoins in moderate to good yields (40%–77%). [ABSTRACT FROM AUTHOR]

In the title molecule, C21H17N3O2, the five-membered ring is slightly ruffled and dihedral angles between the pendant six-membered rings and the central, fivemembered ring vary between 50.78 (4) and 86.78 (10)°. The exocyclic nitrogen lone pair is involved in conjugated π bonding to the five-membered ring. In the crystal, a layered structure is generated by O--H...N and N--H...O hydrogen bonds plus C--H...π(ring) and weak π-stacking interactions. [ABSTRACT FROM AUTHOR]

We herein report a protocol for the asymmetric 1,4‐addition of hydantoins to various Michael acceptors by utilizing Cinchona alkaloid‐based chiral quaternary ammonium salt catalysts. Various products were obtained with moderate to good enantioselectivities and accompanying computational investigations helped to identify key interactions responsible for the observed selectivity. DFT calculations along with non‐covalent interaction plots reveal the presence of numerous stabilizing non‐classical hydrogen bonding interactions along with other non‐covalent interactions between the chiral quaternary ammonium salt and hydantoin molecule in the C−C bond forming transition states leading to the formation of the products. In addition, a first proof‐of‐concept for an analogous a‐sulfanylation reaction, albeit with poor selectivity, is reported as well. [ABSTRACT FROM AUTHOR]

[Display omitted] Poly (vinyl alcohol) (PVA) cryogels can be functionalized with n -Halamines to confer biocidal features useful for their application as wound-dressing tools. Their efficacy can be boosted by stably embedding a polymeric bacterial food source (e.g., starch) in the gel matrix. The bioavailability of the food source lures bacteria inside the gel network via chemotactic mechanisms, promoting their contact with the biocidal functionalities and their consequent inactivation. The synthesis of a novel hydantoin-functionalized PVA (H-PVA-hyd) is proposed. The newly synthesized H-PVA-hyd polymer was introduced in the formulation of H-PVA-based cryogels. To promote the cryogelation of the systems we exploited phase-separation mechanisms employing either a PVA carrying residual acetate groups (L-PVA) or starch as phase-segregating components. The permanence of the biocidal functionality after swelling was investigated via proton nuclear magnetic resonance (1H NMR) and Fourier transform infrared (FT-IR) microscopy. The activated H-PVA-hyd cryogels have been tested against bacteria with amylolytic activity (Bacillus subtilis) and the outcomes were analyzed by direct observation via confocal laser scanning microscopy (CLSM). The cryogels containing starch resulted in being the most effective (up to 90% bacterial killing), despite carrying a lower amount of hydantoin groups than their starch-free counterparts, suggesting that their improved efficacy relies on a "Trojan Horse" type of mechanism. [ABSTRACT FROM AUTHOR]

Urea and thiourea formed relatively stable liquid deep eutectic mixtures with KOH at certain ratios. These mixtures showed high activity in the reaction with benzils, quickly forming hydantoins and thiohydantoins in high yields. [ABSTRACT FROM AUTHOR]

The permanent crosslinked network imparts chemical and mechanical stability to crosslinked elastomers, making their recycling a serious environmental issue. The decomposition products of pentaaryl diazoxide in the structure of hydantoin epoxy resin are nitrogen and carbon dioxide, and it is an environmentally friendly resin material. Here, we demonstrate a reversible covalent bonding reaction catalyzed by Zn2+ between the ester bond formed by the hydantoin epoxy resin and the acid anhydride, and construct a reversible crosslinked network structure of the environmentally friendly acid anhydride/hydantoin epoxy resin material. The strength, hardness and toughness of the cured material are greatly improved by optimizing its ratio. The ester exchange bonding can be reversible with temperature, which leads to the shape memory capability of the synthesized cured material. The cured product of HMY1 was recovered with ethylene glycol and completely dissolved at 180°C for 11 h. Ethylene glycol was volatilized at 190°C to obtain decomposed epoxy oligomer (DEO), which was added to the HMY1 resin system (the amount of DEO was 30 wt% of the total mass of the resin), and the network structure was cross‐linked to enable it to be recovered and remanufactured. Thus, this work provides a new avenue for the environmentally friendly development of recyclable, reconfigurable, and thermally adaptable shape‐memory hydantoin epoxy materials. Highlights: Hydantoin epoxy resin eventually breaks down into non‐toxic CO2 and N2.Hydantoin epoxy and methyl tetrahydrophthalic anhydride form a reversible dynamic chemical bond catalyzed by Zn2+.Ethylene glycol can recover and reuse the solidified product. [ABSTRACT FROM AUTHOR]

For the first time, we synthesized three types of cationic linear N-chloramines that do not use the popular 5,5-dimethyl hydantoin scaffold. The characterized N-chloramines displayed satisfactory bactericidal activity, and the long-chain analogues exerted greatly elevated biocidal efficacy due to "synergistic" antibacterial actions between the N–Cl moiety and long chain cationic center. Our study provides highly efficacious biocides as well as paving the way for producing novel N-chloramines that exclude toxic cyanide salts. [ABSTRACT FROM AUTHOR]

The use of diaryliodonium salts in organic reactions has rapidly increased in the last decade because of their efficiency in arylation reactions. Despite this, mechanistic investigations are still scarce, particularly for copper catalyzed N‐arylation reactions. Recently, we published the use of the unsymmetrical aryl(TMP)iodonium salts (TMP=2,4,6‐trimethoxyphenyl) for the selective Cu‐catalyzed N‐arylation of hydantoins. In this work, the mechanism of this reaction has been studied by DFT methods, and our results have been compared with previous and new experimental data. In contrast to the mechanism proposed for C−H arylation reactions, our results suggest that deprotonation of hydantoin precedes the oxidative addition of aryl(TMP)iodonium salt, with the oxidative addition to a Cu(I) imido intermediate and ligand rearrangements being the rate‐limiting steps. This mechanism agrees with the species observed by NMR spectroscopy, kinetic isotope experiments, and the product yields observed using aryl(TMP)iodonium salts with different steric and electronic properties. In addition, it gives some hints for increasing the efficiency of arylation reactions by tuning the diaryliodonium salt. [ABSTRACT FROM AUTHOR]

Regio- and stereoselective cleavage of derived camphor α-diketones bearing functional group at the bridgehead position under Bucherer–Bergs reaction conditions was studied for a range of model compounds that are easily accessible from naturally occurring feedstock. In all cases, cleavage of the carbon–carbon bond between the carbonyl groups led to the formation of functionalized hydantoins containing cyclopentane moiety in their structures. Products were obtained in high yields with no purification required, warranting the use of this methodology for the development of libraries of biorelevant compounds. [ABSTRACT FROM AUTHOR]

In this work, a new PEGylated magnetic carbon nanotube was developed for efficient and safe delivery of poorly water-soluble platinum anticancer drugs. Nanocarriers based on PEGylated magnetic carbon nanotubes were chemically synthesized through simple methods and finally platinum(II) complex conjugated to the synthesized delivery system (carbon nanotubes/polyethyleneglycol@Fe3O4/CPTMS@Cis-dichloro-bis(5-(4-pyridyl)-5-phenylhydantoin)platinum(II)) (CNTs/PEG@M/CPTMS@CisPt(II)). This nanomaterial was characterized by Transmission electron microscopes (TEM), Scanning electron microscopy (SEM), Energy-dispersive X-ray spectroscopy (EDS), X-Ray diffraction analysis (XRD), Ultraviolet–visible (UV–Vis) spectroscopy, Inductively coupled plasma mass spectrometry (ICP-MS), Fourier-transform infrared spectroscopy (FT-IR), Elemental mapping, Raman spectroscopy, and Nuclear Magnetic Resonance (NMR) analysis. The pattern of drug release from the CNTs/PEG@M/CPTMS@CisPt(II) was affected by pH at a certain temperature and time. In vitro cytotoxicity studies shown that despite the acceptable biocompatibility of the drug-free carrier, the drug-conjugated carrier has a good efficiency in limiting the growth and killing cancer cells. These findings revealed that CNTs/PEG@M/CPTMS@CisPt(II) carrier may provide a promising approach for delivery of the anticancer drugs to cancer cells.

This work presents the synthesis, characterization and evaluation of a series of new multifunctional N-substituted hydantoin derivatives for their antibacterial and antifungal activity. Elemental analysis, 1H NMR, 13C NMR, and mass spectroscopy were used to confirm the newly synthesized compounds' structure. The antibacterial and antifungal properties of each synthesized molecule were examined. The examined compounds showed significant to moderate antimicrobial activity against the tested Gram-positive, Gram-negative, and fungal strains with MIC values ranging from 10.3 to 84.2 µM. Compounds 22 (MIC: 11.7–13.5 µM) and 25 (MIC: 10.2–11.9 µM) demonstrated an impressive MIC value against the tested bacterial and fungal strains when compared to the reference medications fluconazole (MIC: 11.7–14.5 µM) and streptomycin (MIC: 14.5 µM), which are broad-spectrum antibiotics and antifungal agents, respectively. Additionally, all of the compounds were tested for their ability to inhibit the phospholipase A2 (PLA2) enzyme, with the IC50 values ranging from 8.53 to 65.14 µM. When compared to the reference drug ursolic acid (IC50: 12.58 µM), compounds 22 (IC50: 10.27 µM) and 25 (IC50: 8.53 µM) were shown to be the most potent PLA2 inhibiting compounds in this series. The findings of the Molecule description with Drug-Likeness Prediction demonstrated that all the compounds are in a linear correlation with Lipinski's rule of five, demonstrating good drug-likeness qualities. The inhibitory effects of the most potent compounds (18, 19, 22 and 25) against the target PLA2 protein (PDB ID: 2H4C) were explained by molecular docking studies. The molecular docking results were in good accord with the experimental findings, and as these compounds had superior binding affinities within the active pocket, they may be classified as potent inhibitors of specific targets.

The Biltz synthesis establishes straightforward access to 5,5‐disubstituted (thio)hydantoins by combining a 1,2‐diketone and a (thio)urea. Its appealing features include inherent atom and step economy together with the potential to generate structurally diverse products. However, control of the stereochemistry of this reaction has proven to be a daunting challenge. Herein, we describe the first example of enantioselective catalytic Biltz synthesis which affords more than 40 thiohydantoins with high stereo‐ and regio‐control, irrespective of the symmetry of thiourea structure. A one pot synthesis of corresponding hydantoins is also documented. Remarkably, experimental studies and DFT calculations establish the reaction pathway and origin of stereoselectivity. [ABSTRACT FROM AUTHOR]

In the current paper, the adiabatic ionization potentials (AIP) for 29 hydantoin derivatives and hydantoin‐based drugs such as allantoin, phenytoin, mephenytoin, nilutamide, iprodione, nitrofurantoin, and ethotoin were calculated using the double hybrid ωB97XD density functional theory (DFT) in coupling with 6‐311+G(2df,2p) basis set at the B3LYP/6‐31+G(d,p) optimized geometry. The neutral and cationic radicals of the examined species were firstly optimized using the B3LYP/6‐31+G(d,p) level. Final energies were improved by single point calculation using 16 different DFT methods such as B3LYP, ωB97, B97D, TPSSTPSS, M06‐2X, ..., and so forth, with 6‐311+G(2df,2p) basis. Statistical tools such as root mean square error (RMSE) was used to examine the accuracy of the DFT method with respect to the standard reference AIP values. These standard references were calculated, for 12 hydantoin derivatives with less than nine non‐hydrogen atoms, by taking the average values of the AIP computed using the G4, G3B3, and CBS‐QBS methods. The vertical ionization potentials (VIPs), the vertical electron affinity (VEA), and global quantum parameters such as electrophilicity and nucleophilicity of the 29 molecules were also calculated. Substitution effect on the AIP, VIP, VEA, fundamental gap, electrophilicity, and nucleophilicity of the species under probe was studied and discussed. The results reveal that substitution of electron withdrawing group (EWG) raises the AIP and VIP, electrophilicity, and the fundamental gap, while substitution of electron donating group (EDG) raises the VEA and the nucleophilicity. Furthermore, the condensed Fukui functions were used to identify the active centers for nucleophilic, electrophilic, and free radical attacks. [ABSTRACT FROM AUTHOR]

Oxidative stress unleashes reactive species capable of oxidizing 2′-deoxyguanosine (G) nucleotides in G-rich sequences of the genome, such as the potential G-quadruplex forming sequencing (PQS) in the NEIL3 gene promoter. Oxidative modification of G yields 8-oxo-7,8-dihydro-2′-deoxyguanosine (OG) that can be further oxidized to hydantoin products. Herein, OG was synthesized into the NEIL3 PQS that was allowed to fold to a G-quadruplex (G4) in K+ ion solutions with varying amounts of Mg2+ in the physiological range. The Mg2+ dependency in the oxidatively modified NEIL3 G4 to stall a replicative DNA polymerase was evaluated. The polymerase was found to stall at the G4 or OG, as well as continue to full-length extension with dependency on the location of the modification and the concentration of Mg2+. To provide some clarity on these findings, OG or the hydantoins were synthesized in model NEIL3 G4 folding sequences at the positions of the polymerase study. The model G4 sequences were allowed to fold in K+ ion solutions with varying levels of Mg2+ to identify how the presence of the divalent metal impacted G4 folding depending on the location of the modification. The presence of Mg2+ either caused the transition of the NEIL3 G4 folds from an antiparallel to parallel orientation of the strands or had no impact. Structural models are proposed to understand the findings using the literature as a guide. The biological significance of the results is discussed. [Display omitted] • Oxidative modification of the NEIL3 promoter G-quadruplex impacts the fold. • The folding of the NEIL3 G-quadruplex when modified has Mg2+-dependent topologies. • DNA polymerase extension is stalled by the modified NEIL3 G-quadruplex with dependency on Mg2+. [ABSTRACT FROM AUTHOR]

In a sustained search for novel potential drug candidates with multispectrum therapeutic application, a series of novel spirooxindoles was designed and synthesized via regioselective three-component reaction between isatin derivatives, 2-phenylglycine and diverse arylidene-imidazolidine-2,4-diones (Hydantoins). The suggested stereochemistry was ascertained by an X-ray diffraction study and NMR spectroscopy. The resulting tetracyclic heterocycles were screened for their in vitro and in vivo anti-inflammatory and analgesic activity and for their in vitro antimicrobial potency. In vitro antibacterial screening revealed that several derivatives exhibited remarkable growth inhibition against different targeted microorganisms. All tested compounds showed excellent activity against the Micrococccus luteus strain (93.75 µg/mL ≤ MIC ≤ 375 µg/mL) as compared to the reference drug tetracycline (MIC = 500 µg/mL). Compound 4e bearing a p-chlorophenyl group on the pyrrolidine ring exhibited the greatest antifungal potential toward Candida albicans and Candida krusei (MIC values of 23.43 µg/mL and 46.87 µg/mL, respectively) as compared to Amphotericin B (MIC = 31.25 and 62.50 µg/mL, respectively). The target compounds were also tested in vitro against the lipoxygenase-5 (LOX-5) enzyme. Compounds 4i and 4l showed significant inhibitory activity with IC50 = 1.09 mg/mL and IC50 = 1.01 mg/mL, respectively, more potent than the parent drug, diclofenac sodium (IC50 = 1.19 mg/mL). In addition, in vivo evaluation of anti-inflammatory and analgesic activity of these spirooxindoles were assessed through carrageenan-induced paw edema and acetic acid-induced writhing assays, respectively, revealing promising results. In silico molecular docking and predictive ADMET studies for the more active spirocompounds were also carried out. [ABSTRACT FROM AUTHOR]

Hydantoin based epoxy resins are a kind of special epoxy resin with nitrogen‐containing five‐membered heterocycle structure but less intensively studied than the common bisphenol A type epoxy resins. Besides, only 5,5‐dimethylhydantoin epoxy resin (DMHR) was paid enough attention among hydantoin based epoxy resins. To understand the reasons behind the above background, in this work, three hydantoin based epoxy resins with different structures but similar epoxy values (0.37–0.40 mol/100 g), including hydantoin epoxy resin (HR), 5,5‐dimethylhydantoin epoxy resin (DMHR), 1,3‐dihydroxymethyl‐5,5‐dimethylhydantoin epoxy resin (DHMDMHR), were synthesized first, their non‐isothermal curing kinetics, thermal and mechanical properties and adhesion performance of the cured products were then investigated and compared with bisphenol A epoxy resin E44. The apparent activation energies of the three hydantoin based epoxy resin/diaminodiphenylmethane (DDM) systems were in the range of 55–59 kJ/mol, slightly higher than that of E44/DDM system (47.1 kJ/mol). The properties of the three cured hydantoin based epoxy resins, such as glass transition temperature, thermal stability, tensile strength and storage modulus, declined with decreasing content of the hydantoin cycles. 5,5‐dimethylhydantoin epoxy resin (DMHR) had the highest adhesion strength (5.6 MPa) among the three hydantoin based epoxy resins, but nearly 60 % lower than that of bisphenol A type E44 epoxy resin (13.2 MPa) when a polyether amine was used as the curing agent. The cured product of E44 epoxy resin was stronger, tougher and thermally more stable than the cured products of the three hydantoin based epoxy resins. While, hydantoin based epoxy resins exhibited superior damping performance than E44 epoxy resin. [ABSTRACT FROM AUTHOR]

Drug-induced gingivitis is caused by the administration of certain drugs such as hydantoin, calcium blockers, beta-blockers, cyclosporine, and oral contraceptives. The aim of this study was to evaluate the modifications linked to drug-induced gingivitis such as changes in color, volume, and consistency, and the clinical signs of periodontal disease.

In this study we report a mild, efficient, scalable, cyanide‐free and environmentally‐benign procedure for synthesizing 5,5‐disubstituted hydantoins starting from alkylnitriles and diethyl carbonate. Synthesis of 5,5‐disubstituted hydantoins is typically carried out under harsh conditions with transition metal catalysts that are not preferable from a sustainability perspective. This procedure illustrates an elegant cyanide‐free synthesis of cyclopropyl‐substituted 5,5‐hydantoins starting from alkylnitriles that circumvent cyanide reagents. This process holds great synthetic relevance owing to the great potential shown by 5,5‐cyclopropyl substituted hydantoins towards treating human osteoarthritis. [ABSTRACT FROM AUTHOR]

In this work, the two novel methods were achieved for the preparation of benzil derivatives 2a--f with high yields and short reaction time from benzoins 1a--f via; (i) their refluxing with a mixture of sulfur and morpholine in ethanol, and (ii) their stirring with oxidizing agent "DMSO-NaBr-H2SO4 system" at 85 °C. Thus, a new series of (5-oxo-4,4-diarylimidazolidin-2-ylidene)cyanamide 3a--f was already synthesized from the reaction of benzils 2a--f with commercially available cyanoguanidine in the presence of sodium ethoxide as a basic catalyst. The new products 3a--f were exhibited promising antioxidant activity based on "in vitro" assays in 2,2-diphenyl-1-picrylhydrazyl (DPPH) compared to vitamin C. [ABSTRACT FROM AUTHOR]

This study reports a mild reaction‐condition approach for the direct C−C bond cleavage of amides to form hydantoin structures in the presence of 4‐methylpyridine and a base. This approach presents an amide C−C bond cleavage strategy enabling nucleophilic addition to the amide carbonyl involving a reactive spiro intermediate. A broad spectrum of pseudo peptide Ugi adducts as bifunctional starting materials was synthesized and used in this transformation. The mechanistic pathway of this reaction was investigated using experimental and theoretical studies. [ABSTRACT FROM AUTHOR]

Historically, formaldehyde was used as a preservative in personal care products to extend product shelf-life; however, given its skin sensitization potential it has been phased out of use and replaced with formaldehyde-releasing preservatives, such as Dimethyloldimethyl hydantoin (DMDMH). A relationship has been established between positive patch test results following exposure to DMDMH and previous sensitization to formaldehyde. Upon direct contact with the skin, formaldehyde can react with skin proteins and cause an acute inflammatory reaction, which may progress to skin sensitization following repeated exposure. This quantitative risk assessment (QRA) aimed to assess the risk of skin sensitization induction following use of shampoo products containing the maximum allowable concentrations of DMDMH in formulation (1% w/v), translating to a free formaldehyde concentration of 0.02%. To determine a margin of safety (MOS) for exposure to DMDMH from use of shampoo products, consumer exposure levels (CEL) were estimated based on typical use scenarios and then benchmarked against an acceptable exposure level (AEL). The AEL was derived using a weight of evidence approach where a range of no expected sensitization induction levels (NESILs) was utilized. The MOS values for a shampoo product containing 1% DMDMH (.02% formaldehyde) was above 1 for the typical use scenario indicating a low likelihood of skin sensitization induction among healthy individuals. Thus, it can be concluded that shampoo products containing DMDMH at or below current allowable concentrations are not expected to increase the risk of skin sensitization induction. [ABSTRACT FROM AUTHOR]

One of the main objectives of peptide drug design is the improvement of peptide pharmacokinetics with maintaining biological activity, which can be achieved by the complex modifications of the primary structure of the peptides. However, these changes often lead to the formation of peculiar impurities in the peptide drugs and their metabolites, which require the development of advanced analytical methods to properly assess their content. Here, we investigated the degradation of the potent long‐acting GnRH antagonist degarelix in various biologic media by the tailor‐made HPLC method, which allows precise determination of 5‐Aph(Hyd)‐degarelix isomer, an impurity found in the degarelix active pharmaceutical ingredient (API) during its manufacturing. Unexpectedly, we discovered a rapid and irreversible conversion of degarelix API into the corresponding hydantoin isomer in serum, suggesting that this impurity can be also a potential drug metabolite in vivo. This finding underlines the importance of the development of more accurate and performing analytical techniques to correctly characterize the chemical composition of the manufactured drugs and their behavior under physiological conditions. [ABSTRACT FROM AUTHOR]

Flaviviridae infections, such as those caused by hepatitis C (HCV) and dengue viruses (DENVs), represent global health risks. Infected people are in danger of developing chronic liver failure or hemorrhagic fever, both of which can be fatal if not treated. The tropical parasites Trypanosoma brucei and Trypanosoma cruzi cause enormous socioeconomic burdens in Sub-Saharan Africa and Latin America. Anti-HCV chemotherapy has severe adverse effects and is expensive, whereas dengue has no clinically authorized treatment. Antiparasitic medicines are often toxic and difficult to administer, and treatment failures are widely reported. There is an urgent need for new chemotherapies. Based on our previous research, we have undertaken structural modification of lead compound V with the goal of producing derivatives with both antiviral and trypanocidal activity. The novel spirocarbocyclic-substituted hydantoin analogs were designed, synthesized, and tested for antiviral activity against three HCV genotypes (1b, 3a, 4a), DENV, yellow fever virus (YFV), and two trypanosome species (T. brucei, T. cruzi). The optimization was successful and led to compounds with significant antiviral and trypanocidal activity and exceptional selectivity. Several modifications were made to further investigate the structure–activity relationships (SARs) and confirm the critical role of lipophilicity and conformational degrees of freedom. [ABSTRACT FROM AUTHOR]

This study investigates the effect of chalcogenides and electron-withdrawing groups CN and F on the optoelectronic properties using DFT and TD-DFT methods, with a focus on the use of a hydantoin anchoring group as an alternative to carboxylic acid-based groups. The results show that the studied dyes have a planar structure that facilitates intramolecular charge transfer and that propeller-shaped terminal phenyl rings help reduce dye aggregation. The maximum absorption was observed between 485 and 627 nanometres, and bathochromic shifts in UV-Vis spectra were observed in the order NH, S, O, Se, and Te for both F- and CN-containing dyes. Excited-state lifetime was highest for dyes containing heavier chalcogenides. Adsorption energies of the dye onto TiO2 anatase (101) with 3 × 6 supercell were found in the range of 0.13–0.79 eV and 0.61–1.54 eV for CN and F-containing dyes, respectively. Dyes featuring Se and Te exhibit superior properties for dye-sensitized solar cell application, and chalcogenide-based dyes are worthy of experimental synthesis. Overall, the study provides valuable insights into the optoelectronic properties of dyes and their potential use in more efficient solar cell technologies. [ABSTRACT FROM AUTHOR]

This paper aims to present the study of obtaining a potential isocyanic bonding agent. The process is based on introducing free isocyanate groups into hydantoin ring. In addition to acting as bonding agents, they can act as curing agents, promoting the formation of cross‐links with the binder so that the propellant cures. The synthesis process consisted of the reaction between toluene diisocyanate (TDI) and 5,5‐dimethylhydantoin (DMH) under different parameters (time, temperature, reaction atmosphere, solvent, and product purification). The reactions were monitored by Fourier transform infrared spectroscopy in the mid‐infrared region (FT‐IR). Furthermore, the product obtained was characterized by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), elemental analysis (CHN), and volumetric chemistry (determination of the isocyanate‐NCO index). Changes in physical characteristics and the results of the determination of index NCO, FT‐IR, TGA, DSC, and CHN analysis indicate that the proposed reactions occurred. It is concluded that, among the parameters studied, those most suitable for the reaction system between isocyanic reagents TDI and DMH are a temperature of 90 °C, coupling of a nitrogen cylinder, and use of toluene solvent in the reaction system. [ABSTRACT FROM AUTHOR]

Microbial contamination of water and air requires novel filtration materials. Here, the disinfecting, nonbleaching compounds 1,3‐dichloro‐5,5‐dimethylhydantoin (DCDMH) and 1‐bromo‐3‐chloro‐5,5‐dimethyl hydantoin (BCDMH) were combined with PAN polymers via electrospinning for antimicrobial filtration. The resulting nanofibrous membranes (PAN/DCDMH and PAN/BCDMH) were fully characterized by SEM, EDS, FTIR, TG, and XPS. Antimicrobial activities of the tested membranes were challenged with E.coli O157:H7 and S.aureus in the aqueous and bioaerosols phase, using the colony counting method. Both types of embedded membranes showed excellent antimicrobial properties upon exposure to bacteria solution and aerosol, and all bacteria were quickly inactivated. The anti‐biofilm activity of embedded membranes was excellent after being treated with bacteria solution for 48 h. In addition, N‐chloramine displayed lower halogen loss than N‐bromamines in air and aqueous conditions. Both DCDMH and BCDMH embedded nanofibrous membranes showed great potential as filtration materials to remove microorganisms from aqueous and air conditions. [ABSTRACT FROM AUTHOR]

5-Alkenyl hydantoins and alkenyl spirohydantoins are converted into bicyclic and tricyclic hydantoins, under indirect electrochemical conditions, generating the phenylselenyl cation in situ. The reactions proceeded in good to exelent yields. The influence of electrochemical conditions on regioand diastereoselectivity of the selenocyclization reactions is investigated. [ABSTRACT FROM AUTHOR]

Chalcones are kin moieties for synthesizing various heterocyclic compounds having medicinal value. Such medicinally importance compounds are Chalcones are flavones, flavanols, pyrimidines, pyrazolines, anthocyanins, thiopyrimidine, benzal coumarones as well as certain compounds like deoxybenzoins and hydantoins which are of some medicinal value. Reaction between p-cresol with 1-(3-chlorophenyl)ethanone gives product 1-(3-(p-tolyloxy)phenyl)ethanone. This product upon condensation with various aromatic aldehyde produced novel chalcones A1-A15. All prepared chalcones A1-A15 were further reflux with Thiourea to give Thiopyrimidones C1-C15. characterizations of all synthesized Thiopyrimidones were done using various spectroscopic techniques such as ¹HNMR & 13CNMR. IR, MASS. [ABSTRACT FROM AUTHOR]

New trifluoromethyl-substituted imidazo[4,5-b][1,4]oxazines were synthesized by the condensation of 4,5-dihydroxy-4,5-bis(trifluoromethyl)imidazolidin-2-one with 2-aminoethanol and 2-aminophenol. An un-usual pathway was observed in the reactions of 1-methyl- and 1-phenyl-4,5-dihydroxy-4,5-bis(trifluoromethyl)-imidazolidin-2-ones with 2-aminoethanol, which led to the formation of 5-[(2-hydroxyethyl)amino]-3-methyl(phenyl)hydantoins. 1-Methyl- and 1-phenyl-4,5-dihydroxy-4,5-bis(trifluoromethyl)imidazolidin-2-ones reacted with 2-aminophenol under similar conditions to give rearrangement products, 5,5-bis(trifluoromethyl)-hydantoins. The molecular structure of 5-[(2-hydroxyethyl)amino]-3-methyl-5-(trifluoromethyl)imidazolidine-2,4-dione was determined by X-ray analysis. [ABSTRACT FROM AUTHOR]

Hybrids of short oligourea foldamers with residues of α, β and γ-amino acids esters at the C-terminus were obtained and subjected to a reaction with LiOH. There are two possible transformations under such conditions, one of which is ester hydrolysis and the formation of a carboxylic group and the other is the cyclization reaction after abstraction of a proton from urea by a base. We have investigated this reaction with difference C-terminal residue structures, as well as under different work-up conditions, especially for oligourea hybrids with α-amino acid esters. For these compounds, an oligourea–hydantoin combination is the product of cyclization. The stability of the hydantoin ring under alkaline conditions has been alsotested. Furthermore, this work reports data related to the structure of C-terminal-modified oligourea foldamers in solution and, for one compound, in the solid state. Helical folding is preserved both for cyclized and linear modifications, with oligourea–acid hybrids appearing to be more conformationally stable, as they are stabilized by an additional intramolecular hydrogen bond in comparison to cyclic derivatives. [ABSTRACT FROM AUTHOR]

Asymmetric catalytic transformations of N‐unprotected cyclic carboxyimides such as succinimides, hydantoins, oxazolidinediones, and glitazones, is a powerful way of directly accessing variety of biologically valuable chiral compounds. Herein, a bis(trichlorosilyl) nucleophilic intermediate formed from cyclic carboxyimides was reacted with aldehydes via (S)‐SEGPHOS dioxide (SEGPHOSO), proceeding the aldol reaction in highly enantioselective fashion through a cyclic transition state. Furthermore, N‐unprotected carboxyimides were chemoselectively activated, even in the presence of N‐alkylated carboxyimides, to undergo stereoselective and chemoselective aldol reactions via in situ silicon tetrachloride activation. The functionalized cyclic carboxyimides is readily derived to the several synthetic units derivatization to various chiral building blocks without unnecessary protection/deprotection steps. [ABSTRACT FROM AUTHOR]

Abstract One of the main objectives of peptide drug design is the improvement of peptide pharmacokinetics with maintaining biological activity, which can be achieved by the complex modifications of the primary structure of the peptides. However, these changes often lead to the formation of peculiar impurities in the peptide drugs and their metabolites, which require the development of advanced analytical methods to properly assess their content. Here, we investigated the degradation of the potent long‐acting GnRH antagonist degarelix in various biologic media by the tailor‐made HPLC method, which allows precise determination of 5‐Aph(Hyd)‐degarelix isomer, an impurity found in the degarelix active pharmaceutical ingredient (API) during its manufacturing. Unexpectedly, we discovered a rapid and irreversible conversion of degarelix API into the corresponding hydantoin isomer in serum, suggesting that this impurity can be also a potential drug metabolite in vivo. This finding underlines the importance of the development of more accurate and performing analytical techniques to correctly characterize the chemical composition of the manufactured drugs and their behavior under physiological conditions.

The Chalcones are intermediate compounds useful for the synthesis of full various heterocyclic compounds such as flavones, flavanols, pyrimidines, pyrazolines, anthocyanins, benzal coumarones as well as certain compounds like deoxybenzoins and hydantoins which are of some therapeutic value. Condensation reaction of p-cresol with 1-(3-chlorophenyl) ethanone gives product 1-(3-(p-tolyloxy)phenyl) ethanone. which upon condensation with various aromatic aldehyde yield novel chalcones A1-A15. All prepared chalcones A1-A15 werefurther reflux with urea to give pyrimidones B1-B15. Characterization of all synthesized pyrimidones were done using various spectroscopic techniques such as 1HNMR, 13C NMR, IR, MASS. [ABSTRACT FROM AUTHOR]

Hydantoin derivatives are commonly used anticonvulsants. In general, they are effective for partialonset seizures and tonic-clonic seizures, but not for absence seizures. Phenytoin is the most important drug in this group, and other drugs, ethotoin, and mephenytoin, are also commonly used to treat epilepsy. Prodrugs such as derivatives have been created. Phenytoin is effective in some cases of trigeminal neuralgia and related neuralgia. Phenytoin is also used to treat arrhythmias. Hydantoins or glycolylureas are heterocyclic organic compounds with the formula CH2C(O)NHC(O)NH. It is a colorless solid formed by the reaction of glycolic acid and urea. It is an oxidized derivative of imidazolidine. In a more general sense, hydantoins can refer to groups and classes of compounds that share the same ring structure as their parent. For example, phenytoin (see below) has two phenyl groups substituted at the 5th carbon of the hydantoin molecule. Actual chemotherapy for epilepsy dates back to the 1850s when "inorganic bromides" were introduced. However, it is worth noting that around the 1920s, the therapeutic and beneficial use of 'phenobarbital' usheredin an era of meaningful treatment of epilepsy. Hydantoin ring chemistry is the synthesis of rings by various methods and their applications in the medical field. Previous descriptions of hydantoin-containing compounds have broad pharmacological and biological activities, including anticancer, anti-inflammatory, anti-immune, antimetabolite, antioxidant, antibacterial, CNS-related, anticonvulsant, antitussive, and cytoprotective activities. [ABSTRACT FROM AUTHOR]

Heterocyclic organic compounds play pivotal roles in drug synthesis and continue to remain a fundamental area of research interest. The present study reports the synthesis, characterization and antibacterial activities of synthesized organic compounds containing pyrazolone and thiohydantoin moieties. Pyrazolone and thiohydantoin scaffolds have been constructed using well-defined methods and their derivatives have been synthesized Structural elucidation has been achieved via IR and NMR spectroscopy techniques. The synthesized compounds have been screened for antimicrobial activity at 50 µg/mL concentration, against three pathogenic micro-organisms, viz: E. coli, K. pneumonia and P. aeruginosa, using the agar diffusion cup plate method. Ciprofloxacin is used as control. Interestingly, all the compounds have exhibited antimicrobial activities. Compound 2b have shown the highest sensitivity against P. aeruginosa with zone of inhibition (ZOI) of 13 mm. Compounds 1a and 2a have shown highest activity against K.pneumonia with ZOI 11 mm each. Compound 2a has shown highest sensitivity against E. coli with ZOI of 8 mm. These findings indicate that the synthesized compounds are pure and possess therapeutic properties. [ABSTRACT FROM AUTHOR]

In a sustained search for novel potential drug candidates with multispectrum therapeutic application, a series of novel spirooxindoles was designed and synthesized via regioselective three-component reaction between isatin derivatives, 2-phenylglycine and diverse arylidene-imidazolidine-2,4-diones (Hydantoins). The suggested stereochemistry was ascertained by an X-ray diffraction study and NMR spectroscopy. The resulting tetracyclic heterocycles were screened for their in vitro and in vivo anti-inflammatory and analgesic activity and for their in vitro antimicrobial potency. In vitro antibacterial screening revealed that several derivatives exhibited remarkable growth inhibition against different targeted microorganisms. All tested compounds showed excellent activity against the Micrococccus luteus strain (93.75 µg/mL ≤ MIC ≤ 375 µg/mL) as compared to the reference drug tetracycline (MIC = 500 µg/mL). Compound 4e bearing a p-chlorophenyl group on the pyrrolidine ring exhibited the greatest antifungal potential toward Candida albicans and Candida krusei (MIC values of 23.43 µg/mL and 46.87 µg/mL, respectively) as compared to Amphotericin B (MIC = 31.25 and 62.50 µg/mL, respectively). The target compounds were also tested in vitro against the lipoxygenase-5 (LOX-5) enzyme. Compounds 4i and 4l showed significant inhibitory activity with IC50 = 1.09 mg/mL and IC50 = 1.01 mg/mL, respectively, more potent than the parent drug, diclofenac sodium (IC50 = 1.19 mg/mL). In addition, in vivo evaluation of anti-inflammatory and analgesic activity of these spirooxindoles were assessed through carrageenan-induced paw edema and acetic acid-induced writhing assays, respectively, revealing promising results. In silico molecular docking and predictive ADMET studies for the more active spirocompounds were also carried out.

A series of novel 1-(4-benzenesulfonamide)-3-alkyl/benzyl-hydantoin derivatives were synthesized and evaluated for the inhibition of eukaryotic and human carbonic anhydrases (CAs, EC 4.2.1.1). The prepared compounds were screened for their hCA inhibitory activities against three cytosolic isoforms as well as two β-CAs from fungal pathogens. The best inhibition was observed against hCA II and VII as well as Candida glabrata enzyme CgNce103. hCA I and Malassezia globosa MgCA enzymes were, on the other hand, less effectively inhibited by these compounds. The inhibitory potency of these compounds against CAs was found to be dependent on the electronic and steric effects of substituent groups on the N3-position of the hydantoin ring, which included alkyl, alkenyl and substituted benzyl moieties. The interesting results against CgNce103 make the compounds of interest for investigations in vivo as potential antifungals. [ABSTRACT FROM AUTHOR]

Introduction: Three novel androgen receptor inhibitors are approved in the USA for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC): apalutamide, enzalutamide, and darolutamide. All three therapies have demonstrated prolonged metastasis-free survival in their respective phase III trials, with differing safety profiles. The objective of this study was to compare the mean per-patient costs of all-cause adverse events (AEs) requiring hospitalization between darolutamide versus apalutamide and enzalutamide for nmCRPC in the USA.Methods: All-cause grade ≥ 3 AEs with corresponding any-grade AEs reported among at least 10% of patients in any arm of the ARAMIS (darolutamide), SPARTAN (apalutamide), and PROSPER (enzalutamide) trials were selected for inclusion in the primary analyses. After matching-adjusted indirect comparison, AE costs were calculated by multiplying the AE rates from the trials by their respective unit costs of hospitalization taken from the US Healthcare Cost and Utilization Project (HCUP) database. Sensitivity analyses which further included any-grade AEs reported among at least 5% of patients were also performed.Results: After reweighting and adjusting for the trials' placebo arms, the mean per-patient AE costs were $1021 and $387 lower for darolutamide than for apalutamide and enzalutamide, respectively, over the trials' duration (SPARTAN and PROSPER, 43 months; ARAMIS, 48 months). For darolutamide vs. apalutamide, the largest drivers of the per-patient cost differences were fracture (adjusted difference $416), hypertension ($143), and rash ($219); for darolutamide vs. enzalutamide, they were fatigue not including asthenia ($290) and hypertension including increased blood pressure (i.e., any AE of hypertension or with elevated blood pressure not yet classified as hypertension) ($60). The results of the sensitivity analyses were consistent with the primary results.Conclusions: Patients with nmCRPC treated with darolutamide in ARAMIS incurred lower AE-related costs (USD), as determined using HCUP costing data, compared with patients treated with either apalutamide (in SPARTAN) or enzalutamide (in PROSPER). [ABSTRACT FROM AUTHOR]

A novel protocol for the efficient synthesis of 1H‐imidazo[5,1‐c][1,4]oxazines has been developed. Aza‐Michael addition of selected primary amines to 1,2‐diaza‐1,3‐dienes (DDs) combined with isothiocyanates or isocyanates in sequential 3‐CR process, affords 2‐thiohydantoins and hydantoins with suitably positioned functional groups to be used for chemoselective acid‐promoted ring‐fused formation. [ABSTRACT FROM AUTHOR]

Castration-resistant prostate cancer (CRPC) is still challenging to treat. Dissatisfaction with androgen signal-targeted therapy forces people to look for other treatment strategies. Therefore, this study is aimed at exploring the role of SOX8/Notch signaling in CRPC. The upregulation of SOX8, Notch4, and Hes5 indicated a poor progression-free survival (PFS) in CRPC patients. The expression of these proteins was also upregulated in enzalutamide-resistant LNCaP cells (Enza-R). Moreover, knocking down SOX8 inhibited malignant biological behaviors and decreased the activation of Notch signaling in Enza-R cells. Importantly, knocking down SOX8 obviously reversed the enzalutamide resistance in Enza-R cells, while RO0429097 (a γ secretase inhibitor inactivates Notch signaling) exerted similar effects. At last, we found that both SOX8 knockdown and/or RO0429097 suppressed tumor growth and bone metastasis in vivo. Altogether, our study indicated that the SOX8/Notch signaling is involved in CRPC and that these enzymes are possible targets to develop novel treatment for CRPC. [ABSTRACT FROM AUTHOR]