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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 H-1, C-13, and N-15 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., IGA/FT/2020/007, Internal Funding Agency of Tomas Bata University in Zlin [IGA/FT/2020/007]

Hydantoin, imidazolidine-2,4-dione, is a non-aromatic five-membered heterocycle, which is considered a valuable, privileged scaffold in medicinal chemistry. The importance of the hydantoin scaffold in drug discovery has been reinforced by several medicines in clinical use, such as phenytoin, nitrofurantoin, and enzalutamide. Hydantoin has five potential substituent sites, including two hydrogen bond acceptors and two hydrogen bond donors. Two additional attractive features of hydantoin scaffolds are their synthetic feasibility for core scaffolds via established cyclization reactions and their ease of accepting various substituents. Because of these characteristics, many hydantoin derivatives with different substituents have been designed and synthesized and exhibit a broad spectrum of biological and pharmacological activities against, for example, cancers, microbial infections, metabolic diseases, and epilepsy. In this review, recent contributions of hydantoin, thiohydantoin, and selenohydantoin scaffolds to medicinal chemistry are described; some major compounds are presented to emphasize their importance, and their structure-activity relationships (SARs) are briefly addressed. Major discussions are devoted to the structural features or novelty of each scaffold and its SAR. The publications in this review encompass those from 2012 to 2018.

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.

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.

Resumo: Reações para obtenção de derivados de hidantoína foram conduzidas a partir de aldeídos de cadeia curta e da 5,5-dimetilhidantoína. O acompanhamento das reações foi realizado por espectroscopia na região do infravermelho médio (MIR) por meio da formação de novas bandas características da estrutura do composto desejado. A análise MIR revelou que estas alterações espectrométricas ocorrem somente na reação com o formaldeído, indicando a formação do produto 1,3-bis(hidroximetil)-5,5-dimetilhidantoína, em presença de água. As bandas de absorção que confirmam a reação foram observadas em 3334 cm-1 (υ OH), 1770 e 1710 cm-1 (υ C=O) e em 1056 cm-1 (υ C-O), sendo esta última, atribuída ao grupo contendo hidroxila primária. A reação da 5,5-dimetil hidantoína com acetaldeído e com propanaldeído não ocorreu sob as condições adotadas neste trabalho. Abstract: Reactions to obtain hydantoin derivatives were carried out with 5,5-dimethylhydantoin and short-chain aldehydes. Monitoring of the reactions was performed using qualitative mid-infrared spectroscopy (MIR) through the formation of new bands characteristic of the desired product. MIR analysis showed that these spectrometric alterations occur only in the reaction with the formaldehyde, indicating the formation of the desired product, 1,3-bis (hydroxymethyl) 5,5-dimethylhydantoin, in the presence of water. The absorption bands that confirmed the reaction were observed at 3334 cm-1 (υ OH), 1770 and 1710 cm-1 (υ C=O) and 1056 cm-1 (υ C-O), the last of which is assigned to the group containing primary hydroxyl.

An effective route to functionalized hydantoin derivatives is described, involving the reaction of a urea derivative resulting from the addition of a primary amine to an arylsulfonyl isocyanate, and an alkyl propiolate or dialkyl acetylenedicarboxylate in the presence of triphenylphosphine. The reactive 1:1 intermediate obtained from the addition of triphenylphosphine to the alkyl propiolate or dialkyl acetylenedicarboxylate was trapped by NH-acids such as the urea derivative to produce functionalized hydantoin derivatives.

Amino-acid-derived ureas (I) and (VI) are modified with pseudoephedrine as a chiral auxiliary to yield compounds (III) and (VII), which undergo LDA-promoted rearrangement including an aryl shift to yield hydantoins (IV) and (VIII).

A survey of Lewis acids was conducted to facilitate the formation of arylidenethiohydantoins. The use of indium(III) triflate shows significant advantages in facilitating this reaction. In most examples, the Lewis acid promoted catalysis gave shorter reaction times, higher conversion, and better purity profiles as compared to the traditional uncatalyzed reactions.

Three procedures were used for the synthesis of α-, β, and γ-pyridyl-substituted (5Z)-3-phenyl-5-(pyridylmethylene)-2-thiohydantoins: the reaction of 2-thiohydantoin with the corresponding aldehyde in AcOH in the presence of AcONa, the two-step one-pot synthesis with the use of the same starting compounds, and three-component condensation of aryl isothiocyanate, glycine, and aldehyde in AcOH. Alkylation of the resulting thiohydantoins with iodomethane in the presence of a base afforded the corresponding S-methylated derivatives, viz., 2-methylthio-3-phenyl-5-(pyridylmethylene)-3,5-dihydro-4H-imidazol-4-ones. The structures of (5Z)-3-phenyl-5-(pyridin-2-ylmethylene)-2-thioxoimidazolin-4-one and (5Z)-2-methylthio-3-phenyl-5-(pyridin-2-ylmethylene)-3,5-dihydro-4H-imidazol-4-one were established by X-ray diffraction analysis.

In the reaction of ethyl isothiocyanatoacetate with diamines, followed by cyclization of the intermediate product, 3-monosubstituted thiohydantoins have been obtained. It was found that the reaction course depends on the purity of the isothiocyanate used and also, in the case of dialkylaminoamines, the self-cyclization occurs. Besides the dialkylamino derivatives of 3-monosubstituted 2-thiohydantoins also new monoalkylamino, amino and heterocyclic derivatives were synthesized. The aryldiazonium derivative of 3-monosubstituted 2-thiohydantoin yielded both respective phenol derivative after hydrolysis and the product of coupling with 2-naphthol.

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

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.

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.

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.

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.

A noncatalyzed conjugate addition reaction of alkylaluminium compounds to 1,3-dibenzyl-5-methylene-2,4-imidazolidinedione 1 led to the exclusive formation of single and double conjugate adducts (2 and 3, respectively). The ratio of 2 : 3 depended on the reaction temperature and the concentration of 1.

Reaction of 2-amino-4-trifluoromethyloxazoles with excess bromine in acetic acid/sodium acetate gives 5-acetoxyhydantoins. The 5-bromooxazoles are intermediates in the reaction.

3-Aryl-5-((Z)-arylidene)-3-aryl-2-(2-methylthioethyl)-2-thiohydantoins 3a–f and 3-aryl-5-((Z)-arylidene)-2-(2′,3′,4′,6′-tetra-O-acetyl-β-d-glucopyranosyl)-2-thiohydantoins 7a–n were prepared from the reaction of 3-aryl-5-((Z)-arylidene)-2-thiohydantoins 2a–n with methylthioethyl chloride or 2′,3′,4′,6′-tetra-O-acetyl-α-d-glucopyranosyl bromide via three different routes. The compounds did not display any antiviral and antitumoral activity.

Some ethyl 5-aryl(or benzyl)-2-oxo-1,3,4-oxadiazole-3(2H)-acetates were prepared and treated with ammonia, primary amines or hydrazine to give 1-amino-2,4-imidazolidinedione or 1,3-diamino-2,4-imidazolidinedione derivatives. The 1,3-bis(benzylideneamino)-,2,4-imidazolidinedione was obtained by reacting ethyl bromoacetate with the 1,5-dibenzylidenecarbonohydrazide sodium salt

New derivatives of the naturally occurring amino acid 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (spinacine) are reported. These include amide, ester, 5-alkyl and acyl, and regiospecific N im -alkyl and aralkyl derivatives. Synthesis via the Pictet-Spengler reaction of N im -substituted histidines is described. Cyclic hydantoin derivatives of spinacines are included

Hydantoin derivatives were obtained by the reactions of terminal alkynes with isocyanates in the presence of a catalytic amount of a manganese complex, MnBr(CO)5. This reaction also proceeded using...

A three-component reaction of aromatic aldehydes, acetonitrile, and 2-thiohydantoins promoted by TiCl4 was discovered, and a different N–C–N bond-forming reaction took place with FeCl3, AlCl3 or BF3·Et2O as promoter. The thiohydantoin derivatives 1 and 3 were synthesized in moderate to high yields. A plausible mechanism for the formation of 1 and 3 is suggested.

A catalyst system formed in situ from bis(2-methylallyl)cycloocta-1,5-dieneruthenium(II) ((cod)Ru[met]2), a phosphine, and scandium(III) trifluoromethanesulfonate (Sc(OTf)3) was found to efficiently catalyze the anti-Markovnikov addition of imides to terminal alkynes, allowing mild and atom-economic synthesis of enimides. Depending on the phosphine employed, both the (E)- and the (Z)-isomer can be accessed stereoselectively.

An effective route to novel hydantoins is described. This involves reaction of dialkyl acetylenedicarboxylates and arylsulfonyl isocyanates in the presence of trialkyl phosphites. Stable crystalline phosphorus ylides are obtained in excellent yields from the 1:1:2 addition reaction between trialkyl phosphites and dialkyl acetylenedicarboxylates in the presence of arylsulfonyl isocyanates. These hydantoin-containing phosphoranes exist in solution as a mixture of two geometrical isomers as a result of restricted rotation around the carbon-carbon double bond resulting from conjugation of the ylide moiety with the adjacent carbonyl group.

Reactions of benzotriazol-1-yl(1H-pyrrol-2-yl)methanone 10 and benzotriazol-1-yl(1H-indol-2-yl)methanone 11 with diverse ketones, isocyanates, and isothiocyanates in the presence of base afforded pyrrolo[1,2-c]oxazol-1-ones 1, oxazolo[3,4-a]indol-1-ones 2, pyrrolo[1,2-c]imidazoles 3, and imidazo[1,5-a]indoles 4 by a simple one-step procedure.

A general synthesis protocol for the generation of tri- and tetrasubstituted 5-carbamoylhydantoins is described. Starting from barbituric acids and following bromination and reaction with primary amines, 5-aminobarbituric acids 3a-s and 8 were prepared. Compounds 3 and 8 were subjected to different conditions of a base-catalyzed rearrangement reaction to yield the 1,5,5-trisubstituted hydantoins 4a-s and the 1,3,5,5-tetrasubstituted hydantoin 5c, respectively. Alkylation of 4a-s afforded 1,3,5,5-tetrasubstituted hydantoins 5a-h. Mechanisms that explain the transformation of corresponding aminobarbituric acids to hydantoins 4a-s and 5c were discussed in terms of the formation of ring-opened intermediates. Aminobarbituric acids 3a-s unsubstituted at position 3 underwent a ring contraction via intermediate isocyanates which were trapped by the amino function. A different mechanism involving a carbamate intermediate was concluded for conversion of the 1,3,5,5-tetrasubstituted aminobarbituric acid 8.

Several 3-Ω-amino monosubstituted hydantoins have been obtained in the reaction of isocyanate of glycine ethyl ester with the appropriate aliphatic or aromatic diamine. It was found, that the 3-(aminoaryl) monosubstituted hydantoins may be diazotized and their diazonium salts may be coupled and hydrolysed without changes in the hydantoin ring.

Hydantoin derivatives were obtained by the reactions of terminal alkynes with isocyanates in the presence of a catalytic amount of a manganese complex, MnBr(CO)5. This reaction also proceeded using...

5-Dialkylaminomethylhydantoins (3) were synthesized from β-aminoalanines (1) as the starting materials in two stages. Intermediate urea derivatives (2) prepared from the addition reaction of β-aminoalanines to phenyl isocyanate are easily cyclized to 5-dialkylaminomethylhydantoins (3) with good yields. The deamination reaction of some of the hydantoin derivatives (3a, 3b) in water were observed and resulted in the formation of 3-phenyl-5-methylenehydantoin (4). The hydantoin derivative (3b) regenerated a urea derivative (2c, d) by treatment with excess amounts of pyrrolidine or piperidine.

The effect of temperature on the rate of alkaline hydrolysis of the monoanions of 2-thioxo-5-arylidenehydantoins was studied. The investigated series obeys an isokinetic law with isokinetic temperature β=321±10°K. The kinetic data obtained constitute evidence that the mechanisms of the hydrolysis of 2-thioxo-5-arylidenehydantoins and their oxygen analogs are identical. A change in the solvation of the starting and transition states is the principal reason for the change in the reactivities of 5-arylidene-2-thioxohydantoins under the influence of the substituent and the temperature as compared with 5-arylidenehydantoins, the N- and Smethyl derivatives, and 4-thioxo-5-benzylidenehydantoin.

Reactions of phenylbromoacetylene with heterocumulenes in the presence of iron pentacarbonyl have been studied. The reactions with arylcarbodiimides gave diazepinone derivatives in 41–17% yields. The reaction with phenyl isocyanate gave two hydantoin derivatives, in 18 and 8% yields. On the other hand, the reaction with diphenylketene was not catalysed by iron pentacarbonyl and gave 2-bromo-3,4-diphenyl-1-diphenylacetoxynaphthalene. In all cases coupling of phenylbromoacetylene to give diphenylbutadiyne was also observed. Reaction mechanisms are discussed.

With aqueous NaOH, the N-cyanoacetyl ureas (III) all cyclize to give the pyrimidine-2,4-diones (IV).

Both protection and sensitization of Mice C57BL against 60Co γ-rays by sulfur-containing amino acid derivatives - S-alkyl-L-cysteines, S-alkyl-2-methyl-DL-cysteines and their hydantoin derivatives, and sulfoxides of these compounds - were examined. DL-5-Allylthiomethyl-5-methylhydantoin (150 mg/kg body weight) had a remarkable radioprotective effect. The survival ratio was 4.33 or above two times as much as that of L-cysteine. On the other hand, its sulfoxide had a radiosensitizing effects; survival ratio, 0.333.

In 1-arylhydantoins an o-methyl group is effectively larger than an o-chloro substituent in restricting rotation about the aryl-C—N bond, whereas in 3-arylhydantoins and 3-aryl-2-thiohydantoins the...

Pharmacokinetics and bioavailability for the 1-benzenesulfonylhydantoin derivatives and 1-unsubstituted hydantoin derivatives were evaluated from the plasma concentrations after oral and intravenous administrations to dogs. Apparent volume of distribution of the 1-benzenesulfonylhydantoin derivatives was about 0.25 l/kg, while that of the 1-unsubstituted hydantoin derivatives was about 1.3 l/kg. The result suggests that introduction of the benzenesulfonyl group at 1-position of the hydantoin ring has marked effect on the distribution into the fluids and tissues of the body. Bioavailabilities of sodium 5,5-diphenylhydantoin and sodium 1-benzenesulfonyl-5,5-diphenylhydantoin exceeded those of their corresponding free forms. The results were well explicable in terms of the excellent dissolution behaviours of the salt forms. The bioavailabilities of 5-ethyl-5-phenylhydantoin and 1-benzenesulfonyl-5-ethyl-5-phenylhydantoin were almost perfect. The results suggest that the dissolution rate is a rate-determining step in the bioavailability of the derivatives having two phenyl groups at 5-position of the hydantoin ring, irrespective of the presence of the benzenesulfonyl group at 1-position.

The cyclization of N-alkylated (arylated) α-ureidocarboxylic acids gives a series of 3-mono- and 3,5-disubstituted hydantoins, and nitrosation of the latter yields their nitroso derivatives. The rotational isomerism of 3-(α-naphthyl)hydantoins has been studied by PMR spectroscopy.

Das Hydantoin (I) reagiert mit 1 Mol der Epoxide (II) in Gegenwart von LiCl oder KCl als Katalysator in DMF, Wasser oder ohne Losungsmittel zu den Monohydroxyalkyl-hydantoinen (III) (70-80% Ausbeute), wahrend bei Reaktion mit einem weiteren Mol (II) die Bis-hydroxyalkyl-Derivate (IV) (75-90%) entstehen.