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[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]

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]

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]

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]

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]

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]

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]