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Anabaenopeptins are common metabolites of cyanobacteria. In the course of reisolation of the known aeruginosins KT608A and KT608B for bioassay studies, we noticed the presence of some unknown anabaenopeptins in the extract of a Microcystis cell mass collected during the 2016 spring bloom event in Lake Kinneret, Israel. The 1H NMR spectra of some of these compounds presented a significant difference in the appearance of the ureido bridge protons, and their molecular masses did not match any one of the 152 known anabaenopeptins. Analyses of the 1D and 2D NMR, HRMS, and MS/MS spectra of the new compounds revealed their structures as the hydantoin derivatives of anabaenopeptins A, B, F, and 1[Dht]-anabaenopeptin A and oscillamide Y (1, 2, 3, 6, and 4, respectively) and a new anabaenopeptin, 1[Dht]-anabaenopeptin A (5). The known anabaenopeptins A, B, and F and oscillamide Y (7, 8, 9, and 10, respectively) were present in the extract as well. We propose that 1–4 and 6 are the possible missing intermediates in the previously proposed partial biosynthesis route to the anabaenopeptins. Compounds 1–6 were tested for inhibition of the serine proteases trypsin and chymotrypsin and found inactive at a final concentration of ca. 54 μM. [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]

Anabaenopeptins are common metabolites of cyanobacteria. In the course of reisolation of the known aeruginosins KT608A and KT608B for bioassay studies, we noticed the presence of some unknown anabaenopeptins in the extract of a Microcystis cell mass collected during the 2016 spring bloom event in Lake Kinneret, Israel. The 1H NMR spectra of some of these compounds presented a significant difference in the appearance of the ureido bridge protons, and their molecular masses did not match any one of the 152 known anabaenopeptins. Analyses of the 1D and 2D NMR, HRMS, and MS/MS spectra of the new compounds revealed their structures as the hydantoin derivatives of anabaenopeptins A, B, F, and 1[Dht]-anabaenopeptin A and oscillamide Y (1, 2, 3, 6, and 4, respectively) and a new anabaenopeptin, 1[Dht]-anabaenopeptin A (5). The known anabaenopeptins A, B, and F and oscillamide Y (7, 8, 9, and 10, respectively) were present in the extract as well. We propose that 1–4 and 6 are the possible missing intermediates in the previously proposed partial biosynthesis route to the anabaenopeptins. Compounds 1–6 were tested for inhibition of the serine proteases trypsin and chymotrypsin and found inactive at a final concentration of ca. 54 μM.

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. [ABSTRACT FROM AUTHOR]

5‐Spirofluorenehydantoin derivatives show efflux modulating, cytotoxic and antiproliferative effects in sensitive and resistant mouse T‐lymphoma cells. In order to extend the knowledge available about the pharmacophoric features responsible for the glycoprotein P (P‐gp) inhibitory properties of arylpiperazine derivatives of 3‐methyl‐5‐spirofluorenehydantoin, we have performed crystal structure analyses for 1‐[3‐(3′‐methyl‐2′,4′‐dioxospiro[fluorene‐9,5′‐imidazolidin]‐1′‐yl)propyl]‐4‐phenylpiperazine‐1,4‐diium dichloride monohydrate, C29H32N4O22+·2Cl−·H2O (1), 3′‐methyl‐1′‐{3‐[4‐(4‐nitrophenyl)piperazin‐1‐yl]propyl}spiro[fluorene‐9,5′‐imidazolidine]‐2′,4′‐dione, C29H29N5O4·H2O (2), 3′‐methyl‐1′‐{5‐[4‐(4‐nitrophenyl)piperazin‐1‐yl]pentyl}spiro[fluorene‐9,5′‐imidazolidine]‐2′,4′‐dione, C31H33N5O4 (3), and 1‐benzyl‐4‐[5‐(3′‐methyl‐2′,4′‐dioxospiro[fluorene‐9,5′‐imidazolidin]‐1′‐yl)pentyl]piperazine‐1,4‐diium dichloride 0.613‐hydrate, C32H38N4O22+·2Cl−·0.613H2O (4). Structure 3 is anhydrous but the other three structures crystallize with water present. The investigated compounds crystallize in the monoclinic crystal system, with the space group P21/n for 1 and 3, and P21/c for 2 and 4. The cations of salts 1 and 4 are doubly protonated, with the protons located on the N atoms of the piperazine rings. The packing of 1 and 4 in the crystals is dominated by intermolecular N—H...Cl and O—H...Cl hydrogen bonds. In the crystal structure of 2, the intermolecular interactions are dominated by O—H...O and O—H...N hydrogen bonds, while in 3, which is lacking in classic hydrogen‐bond donors, it is C—H...O contacts that dominate. Additionally, we have performed induced‐fit docking studies for the investigated compounds docked to the P‐gp human homology model. [ABSTRACT FROM AUTHOR]

[Display omitted] • Six new hydantoins derivatives were designed, synthesized and evaluated for their in vitro antiplasmodial activity. • The most active compound 2c showed excellent inhibitory activity on the tested plasmodium 3D7 strain with an IC 50 value of 3.97 ± 0.01 nM, which was three-fold better than that of chloroquine. • Substitution with a different R group at the N -5 position of the hydantoin scaffold resulted in a marked decrease in antimalarial potency. • All hydantoins derivatives tested were inactive against human MCR-5 normal cells with IC 50 values exceeding 100 μM. Malaria, a devastating disease, has claimed numerous lives and caused considerable suffering, with young children and pregnant women being the most severely affected group. However, the emergence of multidrug-resistant strains of Plasmodium and the adverse side effects associated with existing antimalarial drugs underscore the urgent need for the development of novel, well-tolerated, and more efficient drugs to combat this global health threat. To address these challenges, six new hydantoins derivatives were synthesized and evaluated for their in vitro antiplasmodial activity. Notably, compound 2c exhibited excellent inhibitory activity against the tested Pf 3D7 strain, with an IC 50 value of 3.97 ± 0.01 nM, three-fold better than chloroquine. Following closely, compound 3b demonstrated an IC 50 value of 27.52 ± 3.37 µM against the Pf 3D7 strain in vitro. Additionally, all the hydantoins derivatives tested showed inactive against human MCR-5 cells, with an IC 50 value exceeding 100 μM. In summary, the hydantoin derivative 2c emerges as a promising candidate for further exploration as an antiplasmodial compound. [ABSTRACT FROM AUTHOR]

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.

A series of new thiazolidine-2,4-dione and hydantoin derivatives were synthesized by Knoevenagel condensation.. The compounds were identified by their melting points, 1H NMR, 13C NMR, and HR-MS spectral data. The in vitro antimycobacterial activity was evaluated against reference strain Mycobacterium tuberculosis H37Rv and compared to that of the first-line antituberculosis drugs isoniazid (INH) and ethambutol (EMB). The new compounds showed promising antimycobacterial activity (MIC ranging from 0.75 to 1.54 µM) and low cytotoxicity in the human embryonic kidney cell line HEK-293T (IC50 > 200 µM). The most potent compounds (IIIa) and (V) could be promising drug candidates for further development. In silico ADME screening revealed the biological potential of all synthesized compounds using SwissADME online biological activity prediction software. Molecular docking studies were carried out as well to confirm the groove mode of binding and receptor-complex interactions. [ABSTRACT FROM AUTHOR]

In this study, a series of synthesized 3-(4-substituted benzyl)-5-isopropyl-5-phenylhydantoin derivatives as a potential antiproliferative and antimigratory agents were investigated. The possible antitumor mechanisms of investigated hydantoin derivatives were examined on human breast cancer cell line MDA-MB-231. The cells were treated with different concentrations of compounds (from 0.01 µM to 100 µM) during 24 h and 72 h. The proliferation index, nitric oxide production, apoptosis rate, and migration capacity were measured. The cell invasion potential was examined by measuring the level of MMP-9 and COX-2 gene expression. All tested compounds expressed antiproliferative activity and induced dose- and time-dependent increase in the level of nitrites. The investigated molecules significantly decreased cell survival rate, migration capacity and the expression levels of genes included in the process of tumor invasion. Obtained data suggest that the tested hydantoin derivatives express considerable antitumor activity by reducing cell division rate, elevating apoptosis level, and inhibiting the motility and invasiveness of breast cancer cells. The results obtained in this study indicate that investigated compounds express potential as a novel chemotherapeutic agents against breast cancer growth and progression. [ABSTRACT FROM AUTHOR]

Having identified novel hydantoin derivatives (compounds 1–5) demonstrating promising photoprotective capacity against UV radiation, and understainding the problem of the biotic and abiotic degradation of UV filters, the aim of the study was to evaluate their metabolic fate with the environmental fungus Cunninghamella echinulata. In parallel, compound 1 in vitro microsomal metabolic pattern was evaluated. Finally, in silico toxicity of test compounds and their biotransformation products was estimated, and parent compounds photostability was assessed. The study demonstrated the capacity for C. echinulata to metabolize 1–5, which were biotransformed to a greater extent than the standard UV filter. O -dealkylation of the side chains attached to the phenyl or hydantoin rings, and hydroxylation of the phenyl ring occurred during microbial transformation. O -dealkylation product was a unique metabolite observed in microsomal biotransformation of 1, being its intrinsic clearance in the medium category range. In silico study demonstrated that compounds 1–5 have low toxicity risk. Among the resulting metabolites, four can increase the risk of reproductive effects as shown by OSIRIS prediction. Noteworthy, all indicated metabolites belong to minor metabolites, except for compound 3 major metabolite. Moreover, the results of the photostability study showed that 1–5 were considered to be photostable. To sum up, the obtained in vitro biotransformation, photostability, and in silico toxicity results encourage further studies on hydantoin derivatives as potential UV photoprotective agents. The presented biotransformation profile of compounds 1–5 by C. echinulata suggests that these compounds may follow a similar biodegradation fate when released into the environment. • C. echinulata metabolized cmp. 1–5 to a greater extent than the standard UV filter. • Parent cmp. have low toxicity theoretical risk. • Cmp. 1–5 were considered to be photostable. • Cmp. 1–5 may follow a similar biodegradation when released into the environment. [ABSTRACT FROM AUTHOR]

We report an efficient synthetic strategy to diverse hydantoins and thiohydantoins involving a three‐component reaction with the aid of deep eutectic solvent. Here, N,N′‐dimethyl urea and N,N′‐dimethyl thiourea play a dual role as reactant and reaction medium along with l‐(+)‐tartaric acid. The three‐component reaction provides an easy access to 5‐amino‐1,3‐dialkyl‐substituted hydantoins and thiohydantoins in good yields. [ABSTRACT FROM AUTHOR]

Wholly 538 clinical samples of blood, burns, sputum, wounds and urine were involved in the current study which was done in 4 hospitals. The isolation and diagnosis of fifty-two Acinetobacter baumannii isolate 36.54% from blood specimens, whereas wounds specimens constituted 23.08%, burns specimens achieved 17.31%, sputum specimens formed 13.46% and a low percentage was in urine specimens which accomplished 9.62%. Totally isolates of bacteria were identified via the biochemical, cultural and microbial characteristics and confirmed via VITEK 2 Compact system. It was found that all (100%) of bacteria isolates were resistant to amoxicillin-clavulanic acid and Cefepime, while Tobramycin was the most effective antibiotic. The isolates displayed the ability of biofilm creation via Microtitration plates method (M.T.P), from the whole number (52) isolates,(33) were producers, such as strong biofilm creators were (15) 45.46% and (18) 54.54% moderate though (19) 36.53% isolates were stately as weak or none biofilm producers. MIC for new hydantoin derivative (C12H13N3O2S) was determined against fifteen isolates were active in MIC values equal to 31.25µg/ml gave (7) A. baumannii isolates, while in MIC, values equal to 62.5µg/ml gave (5) isolates, and three isolates were active in MIC values equal to 125µg/ml. [ABSTRACT FROM AUTHOR]

The interaction of 3-amino-5,5′-dimethylhydantoin with nickel and zinc ions was investigated at different conditions by means of UV–Vis, FTIR spectroscopy and electrochemical methods as well as DFT quantum chemical calculations. Through calculated DFT frequencies and experimental FTIR spectra of the complexes the correlation analysis has been made. NBO analysis of the ligand and complexes provides the information about intramolecular resonance stabilization energy and charge transfer between ligand and metal ions. First derivative UV–Vis spectra were done in order to resolve the π→π* and n→π* carbonyl electron transitions of the ligand and complexes. We have shown that complexes with 1:2 stoichiometry were formed at pH closed to physiological. The stability constant was determined for 3-amino-5,5′-dimethylhydantoin ( L ) and Ni(II) ions using differential pulse polarography data. The existence of one complex ( n ¯ = 2) is proved in the presence of high ligand concentration (C L  = 2 × 10 −3 ÷ 6 × 10 −3  mol L −1 ) and the values of the total constant is: lgβ NI ( II ) - L = 9 . 5 ± 0 . 4 (I = 0.1). The UV–Vis spectroscopy and DFT calculations confirm the stoichiometry of the complexes. The results of the study are useful for incorporation with chemical equilibrium models for evaluation of the speciation and the reactions of metals with hydantoin derivatives in order to develop methods for determination of these metals in different milieu. [ABSTRACT FROM AUTHOR]

A new natural product meyeniihydantoin A ( 1 ), and two new hydantoin derivatives, named meyeniihydantoins B–C ( 2 – 3 ) were isolated from the roots of Lepidium meyenii . Their structures were characterized by means of extensive spectroscopic analyses. The isolated meyeniihydantoins were evaluated for their cytotoxicities on NB4, A549, SHSY5Y, PC3 and MCF7 human cancer cell lines. [ABSTRACT FROM AUTHOR]

Four new compounds, including two hydantoin derivatives, macahydantoins C and D ( 1 , 2 ), one urea derivative, macaurea A ( 3 ) and one thioamide analogue, macathioamide A ( 4 ), were isolated from the tube of Lepidium meyenii (Maca). Their chemical structures were determined by analyzing spectroscopic data, especially 1D and 2D NMR spectra, and comparing their specific rotation with data reported in literature. All of the isolates were obtained from plants for the first time. [ABSTRACT FROM AUTHOR]

Some hydantoin derivatives namely, 1-methylhydantoin (MHYD), 5,5-dimethyl-hydantoin (DMHYD), hydantoin-5-acetic acid (HYDAC), 1,3-dibromo-5,5-dimethylhydantoin (DBDMHYD), 5-methyl-5-phenylhydantoin (MPHYD), and hydantoin (HYD) were studied as corrosion inhibitors for mild steel in 0.5 M HCl using experimental and theoretical methods. Tafel polarization measurements showed that the hydantoin derivatives are mixed type inhibitors and obeyed the Langmuir adsorption isotherm model. Scanning electron microscopy (SEM) analyses of surface morphology suggested that the hydantoin derivatives protect mild steel surface in 0.5 M HCl. Quantum chemical calculations and molecular dynamic simulations results were in good agreement with the experimental results. Quantitative structure activity relationship studies showed that the inhibitive performances of the studied compounds correlated well with their molecular weights, frontier molecular orbitals energy gap, fraction of electron transferred and binding energy. [ABSTRACT FROM AUTHOR]

Six new compounds including four tyrosine derivatives ( 1 – 4 ), and two hydantoin derivatives ( 5 – 6 ) were obtained from the investigation of the endophytic fungus Phoma herbarum PSU-H256, which was isolated from a leaf of Hevea brasiliensis . Their structures were determined by analysis of spectroscopic data, especially 1D and 2D NMR. The relative configurations were assigned using NOEDIFF data while the absolute configurations were established by comparison of the optical rotations and circular dichroism data with those of structurally related compounds. [ABSTRACT FROM AUTHOR]

To obtain an insight into the interactions of potential anticonvulsant drugs with their surrounding, two series of 5-methyl-5-aryl- and 5-ethyl-5-arylhydantoins were synthesized and their absorption spectra were recorded in the region from 200 to 400 nm in a set of selected solvents. The effects of solvent dipolarity/polarizability and solvent-solute hydrogen bonding interactions on the absorption maxima shifts were analyzed by means of the linear solvation energy relationship (LSER) concept of Kamlet and Taft. The ratio of the contributions of specific and nonspecific solvent-solute interactions were correlated with the corresponding ADME properties of the studied compounds. The correlation equations were combined with different physicochemical parameters to generate new equations, which demonstrate the reasonable relationships between solvent-solute interactions and the structure-activity parameters. [Projekat Ministarstva nauke Republike Srbije, br. 172013]

Six new polyamides 5a-f containing flexible trimethylene segments in the main chain were synthesized through the direct polycondensation reaction of 1,3-bis(4-carboxy phenoxy) propane 3 with six derivatives of hydantoins 5a-f in a medium consisting of N-methyl-2-pyrrolidone, triphenyl phosphite, calcium chloride and pyridine. The polycondensation reaction produced a series of novel polyamides in high yield with inherent viscosities between 0.30-0.47 dL/g. The resulted polymers were fully characterized by means of FT-IR, 1H-NMR spectroscopy, elemental analyses, inherent viscosity, solubility tests and gel permeation chromatography (GPC). Thermal properties of these polymers were investigated by using thermal gravimetric analysis (TGA) and differential thermal gravimetry (DTG). The glass-transition temperatures of these polyamides were recorded between 130 and 155 oC by differential scanning calorimetry (DSC), and the 5% weight loss temperatures were ranging from 325 to 415 oC under nitrogen. 1,3-bis(4-Carboxy phenoxy) propane 3 was prepared from the reaction of 4-hydroxy benzoic acid 1 with 1,3-dibromo propane 2 in the presence of NaOH solution.

The title compound, C13H13N2O3, a hydantoin derivative, crystallized with two molecules (A and B) in an asymmetric unit. In molecule A, the imidazolidine ring is twisted about the C—N bond involving the spiro C atom, while in molecule B this ring is flat (r.m.s. deviation = 0.010 Å). The pyran rings in both molecules have distorted half-chair conformations. The mean plane of the imidazolidine ring is inclined to the aromatic ring of the chroman unit by 79.71 (11)° in molecule A and 82.83 (12)° in molecule B. In the crystal, pairs of N—H...O hydrogen bonds link the individual molecules to form A–A and B–B inversion dimers. The dimers are linked via N—H...O and C—H...O hydrogen bonds, forming sheets lying parallel to the bc plane, viz. (011). Within the sheets, the A and B molecules are linked by C—H...π interactions.

An unexpected reaction between 4-phenylurazole and fumaric esters which led to the formation of 5-alkylidene derivatives of hydantoin is described in this paper. The reaction takes place in the presence of tetrabutylammonium bromide (TBAB), and 1,4-diaza-bicyclo[2,2,2]octane (DABCO) at 70 °C under solvent-free conditions. [ABSTRACT FROM AUTHOR]

In the title compound, C13H14N2O2, the C5 ring has an envelope conformation with the C atom adjacent to the quaternary C being the flap. The five atoms comprising the imidazolidine-2,4-dione ring are almost planar (r.m.s. deviation = 0.004 Å). The dihedral angle between the five-membered rings is 89.66 (10)°. In the crystal, inversion-related molecules are connected via {...HNCO}2 synthons. These are linked into a helical supramolecular chain along [010] by C—H...O interactions.

Abstract: The potential of α-amino nitrile-derived ureas for the synthesis of imidazolidin-2-one derivatives has been studied in the context of a medicinal chemistry project focused on the search of antagonists of the thrombin receptor PAR1. In this study α-amino nitrile-derived ureas have shown chameleonic reactivity. Thus, under neutral, basic or mild acid media they cyclize to 4-iminoimidazolidin-2-one derivatives, which tautomerize to 4-amino-2,3-dihydro-1H-imidazol-2-ones. This tautomerism triggers epimerization at the C5 of the imidazolidine ring, as well as its oxidation. However, they give stable highly functionalized hydantoin derivatives under strong acid media, by a no-epimerizing two-step hydrolysis. [Copyright &y& Elsevier]

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Considering the importance of hydantoin derivatives in treatment of status epilepticus, four 5-phenylhydantoins, whose lipophilicities were estimated to be similar to that of phenytoin, were synthesized. Evaluation of their anticonvulsant activities was performed on rats by subcutaneous pentylenetetrazol seizure test and intravenous pentylenetetrazol threshold test, and spontaneous locomotor activity test was used to assess possible sedative effects. X-ray analysis of three compounds suggested that certain analogies might be drawn between interactions in crystal packing and biological interactions responsible for their anticonvulsant activity. It was found that 5-ethyl-5-phenyl-3-propylhydantoin exhibits the most favorable pharmacological properties among the synthesized compounds, i.e., anticonvulsant activity comparable to phenytoin with lower liability for induction of sedation in rats. Graphical Abstract: [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Abstract: The study is focused on a series of 5-arylidenehydantoin derivatives with a phenylpiperazine-hydroxypropyl fragment at N3 of the hydantoin ring. The compounds were assessed on their affinity for α1-adrenoceptors and evaluated in functional bioassays for their antagonistic properties. Crystal structures of (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-hydroxypropyl)imidazolidine-2,4-dione (7) and hydrochloride of (Z)-5-(4-chlorobenzylidene)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)imidazolidine-2,4-dione (10a) were solved using the X-ray diffraction method. Classical molecular mechanics (MMFFs force field, MCMM, MacroModel) were used to predict 3D structure of compounds 5a–18a using a crystal structure of 7. SAR analysis was performed on the basis of Barbaro’s pharmacophore model and structural properties of previously investigated α1-adrenoceptor antagonists possessing a hydantoin fragment. Most of the compounds exhibited significant affinities for α1-ARs in nanomolar range (40–290nM). The highest activities (K i <75nM) were observed for compounds possessing a 2-alkoxyphenylpiperazine fragment and two methoxy substituents at the benzylidene moiety. The results indicated that chemical properties, number and positions of substituents at the 5-arylidene fragment influenced the power of α1-affinities as follows: 3,4-di CH3O>2,4-di CH3O>4-Cl>2,3-di CH3O>H>4-N(CH3)2. [Copyright &y& Elsevier]

Abstract: A series of new 5,5-diphenylhydantoin derivatives with various amine–alkyl terminal fragments at N1-position were synthesized. Then a series of twenty-eight compounds with the same hydantoin scaffold were evaluated for their potency to combat bacterial MultiDrug Resistance (MDR). Intrinsic antibacterial activities were first evaluated. As these compounds showed no direct activity on bacteria, their influence on minimal inhibitory concentration (MIC) of nalidixic acid was tested in two strains of Enterobacter aerogenes: the reference-strain ATCC-13048 and the CM-64 strain which over-produces AcrAB-TolC efflux pump. The compounds showed moderate- or low- anti-MDR properties. According to SAR-studies, hit compounds containing 2-methoxyphenylpiperazine at N1-terminal fragment and methylcarboxyl acid one at N3-position of hydantoin have been identified for further microbiological studies and pharmacomodulations to develop efflux pump inhibitors. [Copyright &y& Elsevier]

The variety of biological activities expressed by aminophosphonic acids bearing hydantoin moiety is surprisingly high. Several applications, in quite different fields such as agriculture and human health, have been reported. This report refers to the investigation of genotoxic and antiproliferative effect of recently synthesized aminophosphonic acids with hydantoin moiety. These effects of the newly synthesized [(5,5-dimethyl-2,4-dioxoimidazolidine-1,3-diyl)dimethyl]diphosphonic acid (2), dimethyl[(5,5-dimethyl-2,4-dioxoimidazolidin-3-yl) aminomethyl]phosphonate and dimethyl[(3-[(dimethoxy-phosphoryl)methyl]amino-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)methyl]phosphonate (4) were investigated for the first time. They exhibited moderate clastogenicity, and high antiproliferative activity on ICR mice bone marrow cells. [ABSTRACT FROM AUTHOR]

1,3-Bis[4,4′-(trimellitimido) phenoxy] propane (6) as a new monomer containing a trimethylene moiety was synthesized using a three-step reaction. First 1,3-bis[4,4′-nitrophenoxy] propane (3) was prepared by reaction of 4-nitrophenol 1 with 1,3-dibromo propane (2) in DMF. Then dinitro (3) was reduced to 1,3-bis[4,4′-aminophenoxy] propane (4) using a solution of sodium sulfite in ethanol. Finally, monomer (6) was prepared by reaction of one equivalent diamine (4) with two equivalents of trimellitic anhydride (5) in a mixture of acetic acid and pyridine (3:2). Then six new poly(amide-imide)s (8a - f) were synthesized through the polycondensation reaction of diacid (6) with six different derivatives of hydantoin (7a - f) in N-methyl-2-pyrrolidone, using triphenylphosphite and pyridine as condensing agents. The polycondensation produced a series of novel poly(amide-imide)s in high yields with inherent viscosities between 0.31 and 0.61 dl/g. The resulting poly(amide-imide)s were characterized by elemental analysis, viscosity measurements, thermogravimetric analysis (TGA and DTG), differential scanning calorimetry, solubility tests and FT-IR spectroscopy. [ABSTRACT FROM AUTHOR]

Two series of 3-(4-substituted benzyl)-5-ethyl-5-phenyl- and 3-(4-substituted benzyl)-5,5-diphenylhydantoins were synthesized and their UV absorption spectra were recorded in the region 200-400 nm in selected solvents of different polarity. The effects of solvent dipolarity/polarizability and solvent/solute hydrogen bonding interactions on the spectral shifts were analyzed by means of the linear solvation energy relationship (LSER) methodology of Kamlet and Taft. The quantitative relationships between hydrogen bonding interactions and the lipophilicity and blood-brain permeation of the studied compounds were discussed. Satisfactory linear dependences were obtained for moderate electron-donating and electron-withdrawing substituents at the benzyl moiety, while the strong electron-withdrawing substituent (NO) significantly modifies the solvation characteristics of the molecule. The paper clearly demonstrates how the solvatochromic comparison method may be applied to estimate the contributions of various modes of solvation to the pharmaceutically relevant properties of these newly synthetized hydantoin derivatives. [ABSTRACT FROM AUTHOR]

Six new poly (amide-imide)s (6a-f ) were prepared under microwave irradiation by polycondensation reaction of diacid chloride (4) with 6 different derivatives of hydantoins (5a-f ) using O-cresol as a microwave absorbent. These new PAIs were obtained in high yield and with inherent viscosities between 0.15 and 0.25 dL/g. The resulting poly(amide-imide)s were characterized by elemental analysis, viscosity measurements, thermal gravimetric analysis (TGA & DTG), solubility test, and FT-IR spectroscopy. N-(4-chlorocarbonyl phenyl) trimellitimide acid chloride (4) was prepared by a 2-step reaction. First trimellitic anhydride (1) was reacted with 4-amino benzoic acid (2) in acetic acid solution and the resulting imide-acid [N-(4-carboxy phenyl) trimellitimide] (3) was obtained in high yield. Then diacid (3) was converted to N-(4-chlorocarbonyl phenyl) trimellitimide acid chloride (4) by reaction with thionyl chloride in the presence of pyridine. [ABSTRACT FROM AUTHOR]

Abstract: In the search for new antiarrhythmic agents, some active 2-methoxyphenylpiperazine derivatives of phenytoin were obtained as a chemical modification of compound AZ-99 (3-ethyl-1-[2-hydroxy-3-(4-phenylpiperazin-1-yl)-propyl]-2,4-dioxo-5,5-diphenylimidazolidine). These compounds possessed structural properties similar to those of α1-adrenoceptor antagonists. In the present study, the affinities of the 2-methoxyphenylpiperazine derivatives (1a–3a) for α1- and α2-adrenoceptors were evaluated using radioligand ([3H]prazosin, [3H]clonidine) binding assays. In the next step, a new series of phenylpiperazine derivatives of phenytoin (4a–16a) containing 2-methoxyphenyl-, 2-ethoxyphenyl-, 2-pyridyl- or 2-furoylpiperazine moiety, as well as, various ester or alkyl substituents at 3-position of hydantoin ring were synthesized. The newly synthesized compounds were tested for their affinity to α1- and α2-adrenoceptors. They have shown affinities for α1-adrenoceptors at nanomolar to submicromolar range. Some compounds were moderately selective ligands of α1-adrenoceptors. Selected compounds (3a–5a, 7a, 13a, 14a) were also evaluated for their α1-adrenoceptor antagonistic properties in functional bioassays. A SAR study indicated that the most active compounds contain 2-alkoxyphenylpiperazine moieties and methyl or 2-methylpropionate substituent at 3-N position in hydantoin. The exchange of 2-alkoxyphenyl moiety into 2-furoyl or 2-pyridyl group significantly decreased affinities for α1-adrenoceptors. Molecular modelling results obtained using conformational analysis CONFLEX and PM5 method for geometry optimization, allowed for comparison of the spatial properties of tested compounds with pharmacophore model created by Barbaro et al. for the ideal α1-adrenoceptor antagonist. [Copyright &y& Elsevier]

Six new polyamides (5a-f ) containing p-phenylenediacrylic and hydantoin moieties in the main chain were prepared by direct polycondensation reaction of 4-phenylenediacrylic acid (3) with 6 different hydantoin derivatives (4a-f ) using thionyl chloride and pyridine as condensing agents and N-methyl-2-pyrolidone as solvent. These new polymers (5a-f ) were obtained in high yield and inherent viscosity between 0.35-0.55 dL/g. The resulting polyamides were characterized by elemental analysis, viscosity measurements, thermal gravimetric analysis (TGA and DTG), solubility test, and FT-IR and UV-vis spectroscopy. 4-Phenylenediacrylic acid (3) was prepared by the reactionof terephthal aldehyde (1) with malonic acid (2) in the presence of pyridine. [ABSTRACT FROM AUTHOR]

We synthesized 2,5-bis[(4-carboxyanilino) carbonyl] pyridine (4) as a new monomer containing pyridyl moiety by using a 2-step reaction. At first 2,5-pyridine dicarboxylic acid (1) was converted to 2,5-pyridine dicarbonyl dichloride (2). Then, diacid 4 was prepared by a condensation reaction of diacid chloride (2) with p-aminobenzoic acid (3). Then, 6 new polyamides (6a-f ) were synthesized through the polycondensation reaction of 2,5-bis[(4-carboxyanilino) carbonyl] pyridine (4) with 6 different derivatives of hydantoins (5a-f ) in a medium consisting of N-methyl-2-pyrrolidone, triphenyl phosphite, calcium chloride, and pyridine. The polycondensation reaction produced a series of novel polyamides containing pyridyl moiety int he main chain in high yield, with inherent viscosities between 0.64 and 1.50 dL g-1. The resulting polymers were fully characterized by means of FT-IR spectroscopy, elemental analysis, inherent viscosity, and solubility tests. Thermal properties of these polymers were investigated using thermal gravimetric analysis (TGA) and differential thermal gravimetry (DTG). All the polymers were soluble at room temperature in polar solvents such as N,N′-dimethylaceamide, N,N′-dimethyl formamide, dimethyl sulfoxide, and N-methyl-2-pyrrolidone. [ABSTRACT FROM AUTHOR]

Bis(p-amidobenzoic acid)-p-phenylene diacrylic acid (6) as a new monomer containing p-phenylenediacryloyl moiety was synthesized by using a 3-step reaction. At first p-phenylenediacrylic acid (3) was prepared by reaction of terephthal aldehyde (1) withmalonic acid (2) in the presence of pyridine, and then diacid 3 was converted to p-phenylenediacryloyl chloride (4) by reaction with thionyl chloride. Finally bis(p-amidobenzoic acid)-p-phenylene diacrylic acid (6) was prepared by the condensation reaction of phenylenediacryloyl chloride (4) with p-aminobenzoic acid (5). Then 6 new polyamides (8a-f ) containing p-phenylenediacryloyl and hydantoin moiety in the main chain were prepared by the direct polycondensation reaction of bis(p-amidobenzoic acid)-p-phenylene diacrylic acid (6) with 6 different hydantoin derivatives (7a-f ) by thionyl chloride, N-methyl-2-pyrolidone and pyridine as condensing agents. These new polymers (8a-f ) were obtained in high yield and inherent viscosity between 0.32-0.50 dL/g. The resulting polyamides were characterized by elemental analysis, viscosity measurements, thermal gravimetric analysis (TGA and DTG), solubility test, FT-IR, and UV-vis spectroscopy. [ABSTRACT FROM AUTHOR]

Facile and rapid polycondensation reactions of N1N'-(pyromellitoyl)-bis-L-leucine diacid chloride I with eight different derivatives of hydantoin compounds 2a-h were developed by using a domestic microwave oven in the presence of a small amount of polar organic medium such as o-cresol. The polycondensation reactions proceeded rapidly, compared with the conventional solution polycondensation, and was completed within 7-10 min, producing a series of novel optically active poly(amide-imide)s 3a-h with high yield and inherent viscosity of 0.35-0.65 dL/g. All of the above polymers were fully characterized by FT-IR, elemental analyses, inherent viscosity (η...), solubility test and specific rotation. Some structural characterization and physical properties of these optically active poly(amide-imide)s are reported. [ABSTRACT FROM AUTHOR]

We have developed facile and rapid polycondensation reactions of N-trimellitylimido-L-leucine diacid a polar chloride 1 with eight different derivatives of hydantoin compounds 2a-h, in the presence of a small amount of organic medium, such as o-cresol, by using a domestic microwave oven. The polycondensation reactions proceeded rapidly-they were complete within 7-9 min-to produce a series of novel optically active poly(amide-imide)s ( 3a-h) in high yield with inherent viscosities of 0.33-0.51 dL/g. We characterized the resulting poly(amide-imide)s by elemental analysis, thermal gravimetric analysis (DSC, TGA, and DTG), and FTIR spectroscopy, and by measuring their viscosities, specific rotations, and solubilities. All of the polymers were soluble at room temperature in polar solvents such as N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, and N-methyl-2-pyrrolidone. [ABSTRACT FROM AUTHOR]

Background: Hydantoin and its newly synthesized derivatives have recently become a focus of interest due to their numerous biological activities and newly emerging beneficial effects in different pathological conditions, including cancer., Objective: The aim of this study was to evaluate the possible anti-tumor mechanisms of a series of newly synthesized 3-(4-substituted benzyl)-5-isopropyl-5-phenylhydantoin derivatives in different aspects of cell physiology of human colon cancer cell line, HCT-116., Methods: The increasing concentrations of derivatives (0.01µM up to 100µM) were applied to cells during 24h, 48h, and 72h after which the evaluation of proliferation, apoptosis, oxidative/anti-oxidative status, nitrite production, and migration/invasion potential of treated cells was performed., Results: All tested compounds expressed the dose- and time-dependent anti-proliferative and pro-apoptotic activities against HCT-116 cells. The investigated derivatives induced a decrease in levels of oxidative stress parameters and an increase in levels of nitrite production by treated cells suggesting their significant antioxidative effects. The cell migration index and expression level of tumor invasion-promoting metalloproteinase- 9 (MMP-9) gene were significantly decreased after treatment with the tested hydantoin derivatives implicating their inhibitory role in colon cancer cell motility and invasion processes. The mRNA level of cyclooxygenase-2 (COX-2) gene as a pro-inflammatory gene related to colorectal carcinogenesis was reduced compared to values in the non-treated control cells indicating the significant anti-inflammatory/anti-tumor effects of these compounds., Conclusion: The obtained results show the significant anti-tumor potential of tested derivatives, especially 3- benzyl-5-isopropyl-5-phenylhydantoin and 3-(4-chlorobenzyl)-5-isopropyl-5-phenylhydantoin, suggesting their potential usage in the development of more effective chemotherapies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)