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A series of hydantoin derivatives has been discovered as highly potent nonpeptide antagonists for the human CCR5 receptor. The synthesis, SAR, and biological profiles of this class of antagonists are described.

(4 R )-2,3- O -Isopropylidene-methylspiro[4,6-dideoxy-α- l - lyxo -hexopyranosid-4,5′-imidazolidin]-2′,4′-dione and (4 R )-2,3- O -isopropylidene-methylspiro[4,6-dideoxy-β- d - ribo -hexopyranosid-4,5′-imidazolidin]-2′,4′-dione were prepared under various reaction conditions starting from methyl 6-deoxy-2,3- O -isopropylidene-α- l - lyxo -hexopyranosid-4-ulose. Corresponding α-amino acids methyl (4 R )-4-amino-4- C -carboxy-4,6-dideoxy-α- l - lyxo -hexopyranoside and methyl (4 R )-4-amino-4- C -carboxy-4,6-dideoxy-β- d - ribo -hexopyranoside were obtained from the above hydantoins by selective acid hydrolysis of the isopropylidene group, followed by basic hydrolysis of the hydantoin ring. The crystal structures of both hydantoin derivatives are also presented.

We report a case of multiple myeloma in a 48-year-old woman treated with phenytoin for 55 months. This association may be fortuitous. The depressive effect of phenytoin on the immune responses, however, could account for the occurrence of the dysglobulinaemia. This case points out the need for periodic examination of serum proteins in patients chronically treated with hydantoin derivatives.

The lipophilicity of a representative number of hydantoin derivatives was experimentally determined by RP-HPLC. The stationary phase of RP-HPLC proved a good model to simulate effects of membrane transport. These experimental values were correlated to theoretically estimated lipophilicity values on the basis of global minima structures of the compounds studied. Both these lipophilicity and structure similarities within a proposed pharmacological model for binding the hydantoin derivatives along the sodium channel were classified with respect to their biological activity.

The treatment of 1-cyanoethyl ureas (I) with sBuLi leads to iminohydantoins (II) as a result of an aryl migration and a cyclization.

Two new series of hydantoin derivatives, 3-(4-substituted benzyl)-5,5-diphenyl- and 3-(4-substituted benzyl)-5-ethyl-5-phenylhydantoins, were synthesized and their antiproliferative activity was tested against human colon cancer HCT-116 and breast cancer MDA-MB-231 cell lines. The presence of different substituents on both hydantoin and benzyl moieties changed the antiproliferative activity of the investigated hydantoins, whereby most of the compounds showed superior antiproliferative activity against MDA-MB-231 than against the HCT-116 cell line. The structure of three compounds was studied by single-crystal X-ray diffraction. The general structural characteristic is the presence of N-H center dot center dot center dot O hydrogen bonds in crystal packings. The molecular geometry and bonding features of the investigated hydantoins in the ground states were calculated using the density functional method. The relationship between structure and antiproliferative activity was discussed. The data presented in this investigation afford guidelines for the preparation of new hydantoin derivatives with greater antiproliferative activity.

In connection with our studies on antibacterial compounds in the class of 5-dialkylaminomethylhydantoins against Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) strains, some molecular modifications were attempted. The antibacterial activities of all of the synthesized hydantoin derivatives were evaluated. Among the hydantoin derivatives designed in this study, C₂-symmetrical twin-drug type compound (7) showed the highest level of antibacterial activity against S. aureus strain.

Unsaturated ketoacids (I) are readily converted into functionalized hydantoins (III) in a low melting mixture of N,N′-dimethylurea and L-tartaric acid.

Several new bis-hydantoins are successfully synthesized via a modified Bucherer—Berg reaction.

Steric factors as well as the nucleophilic character of the amino moiety in the isocyanate play an important role in the outcome of the reaction with α-azide esters.

The reaction of aminonitriles (I) with isocyanates leads to desired ureas (III) in high isolated yields, whilst crude ureas derived from aminonitriles (IV) are prone to a cyclization during chromatographic purification affording hydantoins (V).

The title reaction proceeds via a trienamine mechanism and gives rise to the formation of spirocyclic compounds (III) and (V) in good yields and excellent stereoselectivities.

The development of new practical and green methods for the synthesis of small heterocycles is an attractive area of research due to the well-known potential of heterocyclic small molecule scaffolds in the drug discovery process. Herein we report a one-pot, three-component sequential procedure for the synthesis of diversely 1,3,5- and 1,3,5,5-substituted hydantoins, in high yields and very mild conditions, using readily accessible starting materials such as azides, iso(thio)cyanates and substituted α-halo-acetic carboxylic acids. This methodology is especially convenient for the synthesis of spiro-hydantoins, which are particularly interesting bioactive compounds in medicinal chemistry.

Treatment of aminoester substrates with aqueous NH3 at room temperature renders possible the access to a library of title compounds whose structure includes an amide and a guanidine functionality.

Aminocatalyzed asymmetric Diels–Alder reaction between 2,4-dienals and rhodanine/hydantoin derivatives via trienamine mechanism has been developed to synthesize various spirocyclic compounds with good yields (up to 98%) and excellent stereoselectivities (up to 99% ee and >19 : 1 dr).

An efficient and versatile method was used for the diastereoselective synthesis of achiral and racemic spirohydantoins based on ketones 4, 5, 7 and 10.

Selective N- and C-alkenylation of hydantoin followed by metathesis allows an easy and efficient access to various spirocyclic and fused bicyclic hydantion derivatives.

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.

To obtain insight into the interactions of potential anticonvulsant drugs with their surroundings, two series of 5-methyl-5-aryland 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 non-specific solvent-solute interactions were correlated with the corresponding absorption, distribution, metabolism, and excretion (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 the solvent-solute interactions and the structure-activity parameters. Da bi se procenio način na koji potencijalni antikonvulzivni lekovi interaguju sa svojim okruženjem, dve serije 5-metil-5-(4-supstituisanih fenil)i 5-etil-5-(4supstituisanih fenil)hidantoina su sintetisane i njihovi apsorpcioni spektri su snimljeni u intervalu talasnih dužina od 200 do 400 nm u setu izabranih rastvarača. Efekti dipolarnosti/polarizabilnosti rastvarača i vodoničnog vezivanja između molekula rastvarača i rastvorene supstance na pomeranje apsorpcionih maksimuma analizirani su primenom metoda linearne korelacije energije solvatacije (LSER), odnosno Kamlet-Taftovom jednačinom. Odnos doprinosa specifičnih i nespecifičnih interakcija između molekula rastvarača i rastvorene supstance korelisani su sa odgovarajućim ADME svojstvima proučavanih jedinjenja. Korelacione jednačine su dalje kombinovane sa različitim fizičko-hemijskim parametrima pri čemu su dobijene nove jednačine koje na zadovoljavajući način opisuju odnose između interakcija između molekula rastvarača i rastvorene supstance i svojstava koja određuju njihovu aktivnost u organizmu.

A novel, three-component process for the preparation of a small library of unprecedented nonracemic N-carbamoyl hydantoins under very mild conditions, as well as the hypothetic mechanism, are presented.

Activated α,β-unsaturated carboxylic acids undergo an unexpected domino condensation/aza-Michael/O→N acyl migration with carbodiimides, producing N,N-disubstituted hydantoins in good yields. An array of structurally varied aspartic acid-derived hydantoins, including some fluorinated derivatives, have been synthesized by this method, whose scope and limits are discussed.

via three-component, one-pot condensation of various isocyanides, isoquinoline, and thiohydantoins

Trisubstituted hydantoins (VI) are obtained in low yields from malonic acid derivative (IV) via activation with oxalyl dichloride and subsequent treatment with aromatic amines.

1,2-Epoxyoctafluorobutane reacted with urea in DMSO and aqueous DMSO, dioxane, and acetonitrile to give 40–42% of 5-hydroxy-5-pentafluoroethylimidazolidine-2,4-dione. 5-Hydroxy-5-tridecafluorohexylimidazolidine-2,4-dione was formed in 54% yield in analogous reaction of 1,2-epoxytridecafluorooctane with urea in aqueous DMSO. The reactions of 1,2-epoxyoctafluorobutane and 1,2-epoxytridecafluorooctane with urea in anhydrous dioxane and acetonitrile unexpectedly afforded heterocyclization products, 2-amino-5-fluoro-5-perfluoroalkyloxazol-4(5H)-ones (yield 11–82%). Fluorine-containing allantoin, 5-tridecafluorohexyl-5-ureidoimidazolidine-2,4-dione (yield 19%), and N-(1-hydroxy-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)-urea (yield 46%) were synthesized for the first time by reaction of 1,2-epoxytridecafluoroctane with urea in DMSO and aqueous DMSO.

The method allows a ready preparation of the pharmaceutically relevant heterocycles in good to excellent yields and high purity.

The chemistry of thiohydantoins has gained increased interest in both synthetic organic chemistry and biological fields. Many of these compounds exhibit considerable biological activities in various fields. This review covers the literature regarding the synthesis, reactions, and applications of such compounds.

4,5-Dihydroxy-1,3-dialkyl-4,5-diarylimidazolidine-2-thione are obtained in good yields from the 1:1 addition reaction between benzil derivatives and thiourea derivatives in the solid phase. These compounds undergo smooth rearrangement followed by a hydrogen shift to produce thiohydantoins in excellent yields.

The method is highly efficient for the preparation of 2-thiohydantoins and 2-iminothiazolidinones.

The [3 + 2] cycloaddition of (1,3) amphoteric aziridine aldehydes [released from dimers (I) and (VII)] with isocyanates provides access towards reduced aziridino-fused hydantoins (III) and (IX), resp., with three contiguous stereocenters.

Title compounds are produced from 5-carboxymethylene hydantoins generated by reaction of carbodiimides and acetylenedicarboxylic acid monoesters under mild conditions.

A novel synthesis of hydantoins with a variety of substituents is achieved by thermal cyclocondensation.

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.

Thiazolidinones (IV) and (VII), thiazolidinediones (V), and imidazolidinediones (IX) are synthesized in one step by three-component condensation of aromatic aldehydes or amines with chloroacetic acid and thiourea or urea.

A novel synthetic route is developed which can be applied to a wide range of aromatic isocyanates and various acrylates.

The adducts produced in the reaction between trialkyl phosphites and acetylenic esters were trapped by thiohydantoins to produce highly functionalized 5-oxo-2-thioxoimidazolidines and 4,5-dihydro-2-(methylthio)-5-oxoimidazoles in good yields.

A new approach to the synthesis of 3,5-disubstituted thiohydantoins, which uses a functionalized ionic liquid as soluble support, is described.

The compounds (I) are screened for their anticonvulsant activity using intraperitoneal maximal electroshock (MES) and subcutaneous pentylenetetrazole seizures tests on mice.

P4S10-induced reaction of urea derivatives with aldehydes results in formation of the title compounds in a short time.

A series of novel 5-(4-hydroxybenzyl)-2-thioxoimidazolidin-4-one esters were synthesized under mild conditions by the reaction of 5-(4-hydroxybenzyl)-2-thioxoimidazolidin-4-one and carboxylic acids with DCC and DMAP as the promoters. Their structures were confirmed by 1 H-NMR, IR, ESI-MS and elemental analysis. The preliminary bioassy results indicated that some of compounds exhibit good herbicidal activity against Zea mays , Triticum aestivum and Arabidopsis thaliana . The further greenhouse test showed that compounds 6 - 16 and 6 - 28 have 60%, 50% and 50% efficacy against Stellaria media, Echinochloa crus-galli and Setaria viridis at 1,000 g/ha , respectively. Keywords: 5-(4-hydroxybenzyl)-2-thioxoimidazolidin-4-one esters; synthesis; herbicidal activity 1. Introduction Hydantoins and 2-thiohydantoin derivatives are an important class of biologically active molecules. They have not only been used in medicinal chemistry as anti-HSV [1], antidiabetic [2,3], or HDL-cholesterol modulators [4], but also used as fungicides [5] and herbicides [6,7] in agrochemical research. Among these hydantoin derivatives, hydantocidin (

1,2-Diaza-1,3-dienes are used for the construction of diversified trisubstituted 1,3,5-hydantoins with a controlled regioselectivity.

A series of acetylene-based hydantoin inhibitors of the TACE enzyme is obtained in a convergent manner.

Twenty new title derivatives are synthesized via conversion of monoester (I) to the corresponding acyl azide, Curtius reaction, followed by reaction of the formed isocyanate with arylacethydrazides (II) to afford the semicarbazides (III), which cyclize upon treatment with a base to provide the spirohydantoins (IV) as racemic mixtures.

Hydantoins, thiohydantoins, and glycocyamidines have been prepared in moderate to excellent yields at room temperature under solvent-free conditions. 3N-amino and carboamide derivatives of hydantoin (7–8) were prepared in single step by condensing benzil with semicarbazide and biuret respectively.