Hydantoin Derivatives Research Articles

Design, synthesis and evaluation of oxazolopyridinone derivatives as quorum sensing inhibitors

The antibiotic crisis is associated with the appearance of multidrug resistant (MDR) pathogens, which has caused severe bacterial infections and imposed a huge burden on modern society. Therefore, there is an urgent need to develop new antibacterial drugs with novel mechanism of action. Here we designed and synthesized three series of benzoxazolone, oxazolopyridinone and 3-(2-hydroxyphenyl)hydantoin derivatives and evaluated their activity as novel quorum sensing (QS) inhibitors. We found that benzoxazolone and oxazolopyridinone derivatives had promising QS inhibitory activity in the minimum inhibitory concentration, pyocyanin and rhamnolipid inhibition assays. In particular, A10 and B20 at 256 μg/mL not only suppressed pyocyanin production regulated by QS in P. aeruginosa PAO1 by 36.55% and 46.90%, respectively, but also showed the strongest rhamnolipid inhibitory activity with the IC50 values of 66.35 and 56.75 µg/mL, respectively. Further studies demonstrated that B20 at 64 μg/mL inhibited biofilm formation in P. aeruginosa PAO1 by 40%, and weakened its swarming motility. More importantly, the bacterial mortality of B20 combined with ciprofloxacin and clarithromycin against P. aeruginosa were 48.27% and 49.79%, respectively, while ciprofloxacin and clarithromycin had only 16.99% and 29.11% of bacterial mortality against P. aeruginosa when used alone. Mechanistic studies indicated that B20 directly inhibited the QS pathway based on the GFP reporter strain assay. Overall, this compound with oxazolopyridinone core could serve as an antibacterial lead of QS inhibitor for further evaluation of its drug-likeness.

Effect of New 2-Thioxoimidazolidin-4-one Compounds against Staphylococcus aureus Clinical Strains and Immunological Markers' Combinations.

Although the structure-activity relationship indicates that the 4-thioxoimidazolidin ring is essential for antibacterial activities and pharmaceutical applications, there were no enough studies on the derivatives of this compound. Evaluating the new hydantoin compounds C5 (3-((2-bromobenzylidene) amino)-2- thioxoimidazolidin-4-one) and C6 (3-((4- methoxybenzylidene) amino)-2-thioxoimidazolidin-4-one) that were prepared against clinical Staphylococcus aureus isolates for antibacterial, antibiofilm, and antihemagglutination activities is the aim of this study. Therefore, the potential clinical resistance of the strains was evaluated by their ability to form biofilms, antibiotic resistance, and agglutinate erythrocytes macroscopically and microscopically; besides, the bacterial biofilm was screened for any association with the patient's serum immunoglobulin levels and complements. Despite the effective concentration for C5 and C6 compounds, which is ≤ 31.25 μg/ml, the reduction rate is not concentration-dependent; it depends on the molecular docking of the hydantoin compounds. Hence, the effect of the minimal inhibitory concentrations (MICs) is variable. In this study, the results for the compounds (with the concentration of 31.25–62.5 μg/mL for C5 and 62.5–125 μg/mL for C6) significantly manifest the antibacteria, antibiofilm, and antihemagglutination effects against the virulent strains of S. aureus due to the high percentage of biofilm inhibition that was caused by the new hydantoin compounds. Besides, time-kill kinetics studies showed that these compounds pose bactericidal action. Overall, this study revealed that the new hydantoin derivatives have an interesting potential as new antibacterial drugs through the inhibition of bacterial adhesion. The infections of these isolates activate the complement system through the lectin pathway. Nevertheless, these compounds can be improved in order to be used at even lower concentrations.

Synthesis of imidazolidine 2,4 – dione derivatives

Synthesis routes to diphenyl hydantoin derivatives in the presence of the benzils; 4,4-dimethylbenzil , 4-methylbenzil , 4,4-bromobenzil , 4-dimethylaminbenzoin and 4-amin-4-nitrobenzoin and ure- give condensation of benzil and urea allowed by benzylic rearrangement.

Chiral Recognition of Hydantoin Derivatives Enabled by Tetraaza Macrocyclic Chiral Solvating Agents Using 1H NMR Spectroscopy.

Enantiomers of a series of hydantoin derivatives were prepared from d- and l-amino acids with p-tolyl isocyanate and 3,5-bis(trifluoromethyl)phenyl isocyanate as guests for chiral recognition by 1H NMR spectroscopy. Meanwhile, several tetraaza macrocyclic compounds were synthesized as chiral solvating agents from d-phenylalanine and (1S,2S)-(+)-1,2-diaminocyclohexane. An uncommon enantiomeric discrimination has been successfully established for hydantoin derivatives, representatives of five-membered N,N-heterocycles, in the presence of tetraaza macrocyclic chiral solvating agents (TAMCSAs) 1a-1c by means of 1H NMR spectroscopy. Several unprecedented nonequivalent chemical shifts (up to 1.309 ppm) were observed in the split 1H NMR spectra. To evaluate practical applications in the determination of enantiomeric excess (ee), the ee values of samples with different optical purities (up to 95% ee) were accurately calculated by the integration of relevant proton peaks. To better understand the chiral discriminating behavior, Job plots of (±)-G1 with TAMCSA 1a were investigated. Furthermore, in order to further explore any underlying intermolecular hydrogen bonding interactions, theoretical calculations of the enantiomers of (S)-G1 and (R)-G1 with TAMCSA 1a were performed by means of the hybrid density functional theory (B3LYP/6-31G*) of the Gaussian 16 program.

Molecular Rearrangement of Pyrazino[2,3-c]quinolin-5(6H)-ones during Their Reaction with Isocyanic Acid.

New tetrahydropyrazino[2,3-c]quinolin-5(6H)-ones were prepared from 3-chloroquinoline-2,4(1H,3H)-diones and ethylene diamine. In their reaction with HNCO, an unprecedented molecular rearrangement produced new types of hydantoin derivatives. All prepared compounds were characterized on the basis of their 1H, 13C, and 15N NMR and ESI mass spectra and some were authenticated by X-ray analysis of single crystalline material. A proposed mechanism for rearrangement is discussed in this essay. The CDK and ABL inhibition activity as well as in vitro cytotoxicity of the prepared compounds was also tested.

Lepidium meyenii (Maca) Roots: UPLC-HRMS, Molecular Docking, and Molecular Dynamics

Lepidium meyenii or Maca is widely cultivated as a health care food supplement due to its nutritional and medicinal properties. Although there are a few in-depth studies evaluating Maca antihypertensive effects, the correlations between the chemical constituents and bioactivity of the plant have not been studied before. Thus, the roots were extracted using different solvents (aqueous, methanol, 50% methanol, and methylene chloride) and investigated for their antihypertensive and antioxidant activities through several in vitro assays. The methanolic extract exhibited the best renin and angiotensin converting enzyme (ACE) inhibitory activities with IC50 values of 24.79 ± 1.3 ng/mL and 22.02 ± 1.1 ng/mL, respectively, along with the highest antioxidant activity. In total, 120 metabolites from different classes, e.g., alkylamides, alkaloids, glucosinolates, organic acids, and hydantoin derivatives, were identified in the methanolic extract using ultrahigh-performance liquid chromatography/high-resolution mass spectrometry (UPLC/HRMS). Molecular docking simulations were used to investigate the potential binding modes and the intermolecular interactions of the identified compounds with ACE and renin active sites. Glucotropaeolin, β-carboline alkaloids, succinic acid, and 2,4-dihydroxy-3,5-cyclopentyl dienoic acid showed the highest affinity to target the ACE with high docking scores (S ranging from −35.32 to −22.51 kcal mol–1) compared to lisinopril (S = −36.64 kcal mol–1). Interestingly, macamides displayed the greatest binding affinity to the active site of renin with docking scores (S ranging from −22.47 to −28.25 kcal mol–1). Further, β-carbolines achieved docking scores comparable to that of the native ligand (S ranging from −13.50 to −20.06 kcal mol–1). Molecular dynamics simulations and MMPBSA were also carried out and confirmed the docking results. Additionally, the computational ADMET study predicted that the compounds attaining promising docking results had proper pharmacokinetics, drug-likeness characteristics, and safe toxicological profiles. Ultimately, our findings revealed that Maca roots could be considered a promising candidate as an antihypertensive drug.

Role of Hydantoin Derivatives in Syntheses of Polyaspartates

Polyaspartates are industrially important resins formed by reactions of N-substituted 2‑aminosuccinates (or, synonymously, N-substituted aspartates) with isocyanates. To obtain sufficiently crosslinked networks, applicable as coatings, bis-aspartates with two secondary NH groups and isocyanates with more than two NCO groups in their molecules must be used. There are two major problems connected with these preparations: (i) bis-aspartates which are mostly synthesized by the aza-Michael addition of NH2 groups of a suitable diamine to C=C bonds of a maleate ester almost always contain a certain amount of a fumarate ester (usually a few percent) as a result of the Z→E isomerization, unavoidably accompanying the addition; this deteriorates the quality of the resulting product; (ii) during the reaction of bis-aspartate with isocyanate, hydantoin rings are often formed to some extent in addition to the desirable three dimensional structures; the presence of these rings decreases the attainable network density. In this review, those properties, syntheses, and reactions of hydantoin are summarized which could be useful for finding conditions to avoid the formation of hydantoin rings.
 Fulltext of this article is available on the website of this Journal.

Evaluation of Two Novel Hydantoin Derivatives Using Reconstructed Human Skin Model EpiskinTM: Perspectives for Application as Potential Sunscreen Agents.

This study aimed to assess two novel 5-arylideneimidazolidine-2,4-dione (hydantoin) derivatives (JH3 and JH10) demonstrating photoprotective activity using the reconstructed human skin model EpiskinTM. The skin permeability, irritation, and phototoxicity of the compounds was evaluated in vitro. Moreover, the in vitro genotoxicity and human metabolism of both compounds was studied. For skin permeation and irritation experiments, the test compounds were incorporated into a formulation. It was shown that JH3 and JH10 display no skin irritation and no phototoxicity. Both compounds did not markedly enhance the frequency of micronuclei in CHO-K1 cells in the micronucleus assay. Preliminary in vitro studies with liver microsomes demonstrated that hydrolysis appears to constitute their important metabolic pathway. EpiskinTM permeability experiments showed that JH3 permeability was lower than or close to currently used UV filters, whereas JH10 had the potential to permeate the skin. Therefore, a restriction of this compound permeability should be obtained by choosing the right vehicle or by optimizing it, which should be addressed in future studies.

Application of predicted fragmentation pathways and fragment ion structures for detecting steroids and selective androgen receptor modulators in dietary supplements using liquid chromatography-quadrupole time-of-flight mass spectrometry.

Dietary supplements advertised to strengthen muscles have earned fame among athletes. However, several products containing unauthorized compounds are often detected, which can cause a public health risk. Particularly, steroids and selective androgen receptor modulators (SARMs) can cause serious side effects as hormone modulators. In this study, we analyzed 15 steroids and 20 SARMs using liquid chromatography-quadrupole time-of-flight mass spectrometry (LC/QTOFMS) to provide fundamental information about fragmentation pathways and fragment ion structures. The optimal conditions of LC/QTOFMS were explored to obtain fragmentation patterns for each compound. The optimal conditions were established by comparing the area and height of the precursor ion peak at 125 or 175 V as a fragmentor energy. Furthermore, the optimized spectra were acquired by applying collision energy ranging from 1 to 50 eV. The energy value was selected under the condition that the mass error of precursor ions was less than 10ppm. The 35 compounds were classified on the basis of their chemical core structures: arylpropionamide (3 compounds), quinolinone (2), pyrrolidinylbenzonitrile (1), indole (2), tropanol (2), phenylaxadaizole (1), hydantoin (2), phenylthiazole (1), nitrothiophene (1) and steroidal derivative (20). Fragmentation pathways and the chemical structure of each product ion were predicted and identified. Furthermore, the obtained structural information was applied to screen seized samples. As a result, 10 seized samples were confirmed to contain one or more SARMs by comparing each precursor ion and fragmentation pattern. The application to real samples for accurate screening indicated that the same fragmentation patterns and product ions as one or more SARM standards were detected and identified in the seized samples advertised as muscle building. Therefore, this study can contribute to ensuring the safety of public health through providing fundamental information about the risk of illegal adulteration.

Electron-donating Effect of Hydantoin Derivative Inhibitor on the Enhanced Anticorrosion Capacity for Mild Steel in Hydrochloric Acid Medium

Electron-donating Effect of Hydantoin Derivative Inhibitor on the Enhanced Anticorrosion Capacity for Mild Steel in Hydrochloric Acid Medium

Synthesis and Spectral Studies of Hydantoin Derivativatives of Imidazo [2,1-b][1,3,4] Thiadiazoles

Abstract: The present article describes the synthesis of Imidazo[2,1-b][1,3,4]thiadiazoles bearing pharmacologically important hydantoin molecules. To synthesize the targeted molecules several imidazothiadiazoles were prepared by condensation of 2- Amino-5-(4-fluorobenzyl)-1,3,4thiadiazole with phenacyl bromides. Which were subsequently subjected to Knoevenagel condensation to afford the hydantoin derivatives. Structures of newly synthesized molecules were confirmed by IR, NMR and Mass spectral studies. Keywords: Thiadiazole, Imidazothiadiazole, hydantoin, Vilsmeier Haack reaction

Design, synthesis and biological evaluation of hydantoin derivatives as Mcl-1 selective inhibitors

As a member of Bcl-2 protein family, myeloid cell leukemia-1 (Mcl-1) plays a critical role in cell apoptosis and has become a promising anti-cancer drug target. Herein, we designed and synthesized a series of hydantoin derivatives as novel Mcl-1 inhibitors based on our previously developed lead compound. Among them, compound M23 and M24 exhibited good binding affinities against Mcl-1 with Ki values of 0.49 μM and 0.33 μM respectively. Especially, compound M23 exhibited good selectivity over Bcl-xL, whereas compound M24 possessed good selectivity over both Bcl-2 and Bcl-xL. Furthermore, we also investigated the effects of these new Mcl-1 inhibitors on cell proliferation, apoptosis and mitochondrial membrane potential, as well as the stability in plasma.

Thermochemical Study of 1-Methylhydantoin.

Using static bomb combustion calorimetry, the combustion energy of 1-methylhydantoin was obtained, from which the standard molar enthalpy of formation of the crystalline phase at T = 298.15 K of the compound studied was calculated. Through thermogravimetry, mass loss rates were measured as a function of temperature, from which the enthalpy of vaporization was calculated. Additionally, some properties of fusion were determined by differential scanning calorimetry, such as enthalpy and temperature. Adding the enthalpy of fusion to the enthalpy of vaporization, the enthalpy of sublimation of the compound was obtained at T = 298.15 K. By combining the enthalpy of formation of the compound in crystalline phase with its enthalpy of sublimation, the respective standard molar enthalpy of formation in the gas phase was calculated. On the other hand, the results obtained in the present work were compared with those of other derivatives of hydantoin, with which the effect of the change of some substituents in the base heterocyclic ring was evaluated.

Antiarrhythmic Effects of Phenytoin, a Novel Heart Failure Diastolic Ryanodine Channel Inhibitor, in Human Failing Ventricle

Heart failure (HF) is a devastating disease and despite advances in medical therapy, mortality remains high due to ventricular arrhythmias. Modifications to the cardiac ryanodine receptor (RyR2) due to stress induced mechanisms ultimately lead to pathological Ca2+ leak during diastole, resulting in delayed after depolarisations and ventricular arrhythmias. Phenytoin, a hydantoin derivative used as an anti-convulsant, is known to exhibit weak Na+ channel blockade in cardiomyocytes. Recent studies revealed that phenytoin inhibits diastolic but not systolic Ca2+ leak from RyR2 channels of human failing hearts and has no effect on Ca2+ release from RyR2 channels from non-failing hearts [1].

Synthesis of series of different imidazolidine-2,4-dione derivatives and evaluation of their antimicrobial potential

A series of twenty two different imidazolidine-2,4-dione derivatives, divided according to their structure into five groups, including alkyl, alkenyl or aryl 5,5disubstituted hydantoins, spirohydantoins, and fused bicyclic and tricyclic hydantoins, was synthesized and examined for in vitro antimicrobial activity against 15 strains of bacteria and 4 strains of yeast. The antimicrobial activity was evaluated by the determination of the minimal inhibitory concentration (MIC) and the minimal microbicidal concentration (MMC) using the microdilution method. The assayed compounds exerted moderate antibacterial and weak antifungal activity. The antimicrobial activities were influenced by the structure and concentration of the tested compounds as well as the type of test microorganisms. The fused bicyclic hydantoin derivatives obtained by organoselenium induced intramolecular cyclization exhibited the highest inhibitory activity. The examined hydantoin derivatives seem as drug-like candidate for further evaluation of biological activities.

Associations between osteoporosis and drug exposure: A post-marketing study of the World Health Organization pharmacovigilance database (VigiBase®).

Bone remodeling is a complex process, and many conditions (including drug exposure) lead to osteoporosis. Here, we sought to detect new disproportionality signals for drugs associated with osteoporosis. We performed a disproportionality analysis of the World Health Organization's VigiBase® pharmacovigilance database through April 12, 2020. The frequency of reports on osteoporosis for all identified drug classes was compared with that for all other drugs and quoted as the reporting odds ratio (ROR) [95% confidence interval (CI)]. Of the 7,594,968 cases spontaneously recorded to VigiBase®, 4758 concerned osteoporosis. New disproportionality signals with a pharmacologically plausible mechanism were found for drugs used in neurology (levodopa (ROR [95%CI]: 10.18 [4.33-25.10]), selective serotonin agonists (4.22 [2.34-7.00]) and memantine (4.10 [1.56-8.93])), hematology (romiplostim (4.93 [1.15-21.10])), pulmonology (macitentan (3.02 [1.84-4.90])), ophthalmology (ranibizumab (3.31 [1.00-10.51])) and rheumatology (tofacitinib (3.65 [3.00-4.40])). The robustness of these new results is supported by the significant RORs for the vast majority of drugs already known to induce osteoporosis and/or increase the fracture risk, namely glucocorticoids, gonadotropin-releasing hormone analogs, anti-aromatases, androgen receptor blockers, thyroid hormones, proton pump inhibitors, thiazolidinediones, vitamin K antagonists, loop diuretics, protease inhibitors, nucleoside and nucleotide reverse transcriptase inhibitors, and enzyme-inducing antiepileptics including barbiturates and derivatives, hydantoin derivatives, carboxamide derivatives and fatty acid derivatives. We established up a comprehensive list of drugs potentially associated with osteoporosis and highlighted those with pharmacologically plausible mechanisms leading to bone fragility. Our results might pave the way for additional exploration of these mechanisms.

Synthesis, crystal structure, hydrogen bond patterns and Hirshfeld surface analysis of (S)-5-(4-hydroxybenzyl)-imidazolidine-2,4‑dione

The title compound, (S)-5-(4-hydroxybenzyl)-imidazolidine-2,4‑dione, a new α-amino acid hydantoin derivative with formula C10H10N2O3 has been synthesized and structurally characterized by MS, FT-IR, NMR, and X-ray diffraction techniques. Spectroscopy results are consistent with the skeleton structure. The powder X-ray diffraction data confirms the phase purity of the crystalline sample. Single-crystal X-ray diffraction analysis indicated that crystallizes in the orthorhombic space group P212121 (N°19), Z = 4, and unit cell parameters a = 6.217(3) Å, b = 7.653(3) Å, c = 19.824(8) Å. The molecular structure and crystal packing are stabilized by intermolecular N–H···O and O–H···O hydrogen formed infinite two-dimensional chains, with graph-set C(6), C(5) and C(11) that run along the a, b and c directions forming a two-dimensional network. Hirshfeld surface analysis confirm that the most important contributions for the crystal packing are from N–H··O and O–H··O interactions. Energy framework calculations suggest that the contacts formed between molecules are slightly electrostatic and revealed that interactions exhibit approximately complex zig-zag shape topology in the crystal structure.

Synthesis and anticancer activity of Pt(II) complexes of spiro-5-substituted 2,4-dithiohydantoins

Despite the widely studied anticancer activity of metal complexes of various hydantoin derivatives, reports on biological properties of dithiohydantoin complexes are limited to only few. Main challenge is determination of their structure, since no crystallographic data are available for metal complexes of dithiohydantoins. Herein, we describe the synthesis and structure of Pt(II) complexes of two spiro-5-(2,4-dihiohydantoins) with large and potentially intercalating aromatic rings, namely 3′,4′-dihydro-2H,2′H,5H-spiro[imidazolidine-4,1′-naphthalene]-2,5-dithione and spiro-(fluorene-9,4′-imidazolidine)-2′,5′-dithione. The anticancer activity of all compounds were tested against HL-60, BV-173, and K-562 tumor cell lines. Single-crystal X-ray analysis was performed for the spiro-(benzocyclohexane-4′-imidazolidine)-2′,5′-dithione, whereas all other compounds were characterized by integrated approach of spectroscopic (IR and solid-state NMR) and theoretical (DFT) studies. The analysis of the data suggested Pt2L4 composition of the complexes with bridging N^S coordination of four ligand molecules and two Pt(II) centers of square planar geometry. Polymeric structure in the solid state was also presumed. The complexes showed modest to moderate anticancer activity as compared to cisplatin and the chronic myeloid leukemia derived BV-173 proved to be the most responsive tumor model.

Preparation of New Spiropyrazole, Pyrazole and Hydantoin Derivatives and Investigation of Their Antioxidant and Antibacterial Activities.

In this study, the synthesis of new spiropyrazoles, pyrazole and hydantoin heterocycles is reported by three component reactions of parabanic acids, hydrazine derivatives, and phenacyl bromides in the presence of triphenylphosphine as a nucleophile and triethylamine as a base in good to high yields (69-91 %). Evaluation of the synthesized compounds revealed a good to excellent antioxidant activities (37.6-96.2 %) using DPPH inhibitory potency. Among these compounds, hydantoin derivatives displayed higher antioxidant activities (93.7-96.2 %) comparing with spiropyrazoles and pyrazoles. The obtained results showed that Cl and Br substituents on the phenyl ring increased antioxidant activities of the related heterocycles. The antibacterial activities of the synthesized compounds were examined against two Gram-negative (Escherichia coli and Pseudomonas aeruginosa) and two Gram-positive (Staphylococcus aureus and Bacillus subtilis) bacteria. Among the synthesized heterocycles, 2-[1,3-dimethyl-2,5-dioxo-4-(2-oxo-2-phenylethyl)imidazolidin-4-yl]hydrazine-1-carbothioamide exhibited the excellent antibacterial activity against both Gram-positive and Gram-negative bacteria.

Design, Synthesis, and In Vitro Antiproliferative Activity of Hydantoin and Purine Derivatives with the 4-Acetylphenylpiperazinylalkyl Moiety.

Cancer represents one of the most serious health problems and the second leading cause of death around the world. Heterocycles, due to their prevalence in nature as well as their structural and chemical diversity, play an immensely important role in anti-cancer drug discovery. In this paper, a series of hydantoin and purine derivatives containing a 4-acetylphenylpiperazinylalkyl moiety were designed, synthesized, and biologically evaluated for their anticancer activity on selected cancer cell lines (PC3, SW480, SW620). Compound 4, a derivative of 3′,4′-dihydro-2′H-spiro[imidazolidine-4,1′-naphthalene]-2,5-dione, was the most effective against SW480, SW620, and PC3 cancer cell lines. Moreover, 4 has high tumor-targeting selectivity. Based on docking studies, it was concluded that R isomers of 3′,4′-dihydro-2′H-spiro[imidazolidine-4,1′-naphthalene]-2,5-dione could be further studied as promising scaffolds for the development of thymidine phosphorylase inhibitors.