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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]

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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.

In connection with our studies on hydantoin derivatives, a conventional regioselective chemical transformation of 5-methylene hydantoins 4a-c to 5-aminomethyl-substituted hydantoins 5-10 or to 5-amino-5-methyl-disubstituted hydantoins 11-14 is described. Synthesis of bivalent twin-drug type hydantoin derivatives 19-24 and the binding property of a bivalent symmetrical hydantoin derivative 24b to sulfated glycosaminoglycans are also described.

The novel and one-pot synthesis of 5-hydroxyl hydantoins from Ugi five-component condensation procedures is reported. The transformation was promoted via a microwave heating method and provided 5-hydroxyl hydantoins in workable yields, representing a direct approach to this synthetically challenging and biologically interesting pharmacophore.

A novel method for the direct synthesis of 5-arylidene-2-thiohydantoins from thioureas and aromatic aldehydes in the presence of base in ethanol was developed. Application of this efficient method allowed preparing thiohydantoins, which are difficult to synthesis by traditional methods.

The reaction of α-keto acids with carbodiimides provides O-acyl urea intermediates which undergo visible light induced rearrangement to form unexpected hydantoine derivatives.

The reaction of 4-phenylurazole and fumaric esters in the presence of tetrabutylammonium bromide results in the formation of 5-alkylidene derivatives of hydantoin under solvent-free conditions.

A mild method to convert optically pure amino acid thiourea and urea derivatives to thiohydantoins and hydantoins, respectively, is described. It provides an efficient way to realize enantioselective synthesis of thiohydantoins and hydantoins with good to high isolated yields and enantiomeric purities. We found that the enantiomeric purities were highly dependent on the reaction conditions including bases, solvents, and temperature.

International audience; A series of new 5,5-diphenylhydantoin derivatives with various amineealkyl 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 pharma-comodulations to develop efflux pump inhibitors.

An efficient procedure for the preparation of 5-dialkylaminomethylhydantoins 3, which are easily obtained from cyclization of the corresponding urea derivatives 2 starting with beta-aminoalanines 1, is described. Methylenehydantoin and the corresponding 2-thio analogue (4a, 4b) were obtained from hydantoins 3a and 3b, respectively. Some new chemical properties of these hydantoin derivatives are reported.

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).

Simple hydrazides and hydrazones are used as precursors of the required N-substituted isocyanates.

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.

We describe here a multicomponent reaction that converts aryl/heteroaryl aldehydes efficiently into arylmethylene 2-thiohydantoins. 3-Formylindole behaves exceptionally giving a gem-diacetylthio derivative. A mechanistic study of the behaviour of 3-formylindole, which provides a new class of indole derivative, is described.

N-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)cyanothioformamide was synthesized from the corresponding 4-amino-pyrazole. Various cyanothioformamides were reacted with different arylidenes of cyanothioacetamide to produce either 4-imino-5-thioxo-3-(pyrroline & pyrrolidine)carbonitrile or pyrrolo[3,2-d]thiazole. Interaction of thiohydantoin with the arylidenes of either malononitrile or cyanothioacetamide furnished the same 5-aminothiopyrano[2,3-d]-imidazole-6-carbonitriles. Also, thiohydantoin reacted with the anilide of chloroacetic acid and with anthranilic acid to produce thieno[2,3-d]-imidazole-2-one and imidazo[4,5-b]quinoline-2,9-dione, respectively.

A facile access to 1,3,5-trisubstituted hydantoins is achieved by combining an Ugi four-component condensation with a base-induced cyclization. This two-step sequence, which differs from any other method; is experimentally simple and allows a wide variety in the substitution pattern. In this synthesis the acid component, namely trichloroacetic acid, acts as a carbonic acid equivalent.

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.

The synthesis of new potential inhibitors of human chymase is described. Treatment of dihydroimidazo[1,5-a]indole and [1,5-b]isoquinoline-dione with thioaryl followed by oxidation gave the N-arylsulfonylmethyl of polycyclic hydantoin derivatives 3, 5 and 6.

The synthetic procedures to obtain indole derivatives with different acidic functions at position 2 of the indole are reported. The synthesised and tested derivatives comprise 5-tetrazolyl, 1,3,4-oxadiazol-5-yl-2-one, and indole-2-carboxylic acid amides with 5-aminotetrazole, methanesulphonamide and trifluoromethanesulphonamide moieties. The binding affinity was evaluated using [3H]MDL 105,519 and pig cortical brain membranes. In general, compounds with acidic functions different from a carboxylic acid moiety are less potent than indole-2-carboxylic acid derivatives. Also, the 4,6-dichloro substitution pattern was compared to 5-tert-butyl derivatives and compounds not substituted in the benzene moiety of the indole, indicating that the affinity increases from 5-tert-butyl over unsubstituted to 4,6-dichloro substituted derivatives.

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 triethylamine mediated reaction of α-bromoacetamides with N-sulfonyl isocyanates gives urea salts which undergo intramolecular cyclization to N-sulfonyl hydantoins under thermal conditions.

The use of cyclododecanone-protected thiosemicarbazide (I) for the synthesis of highly functionalized 3-amino-2-thiohydantoins (IV) is demonstrated.

Base-promoted facile synthesis of thiohydantoins has been described via intramolecular amidolysis of C-3 functionalized 2-azetidinones. This approach provides a convenient and rapid access to diversely functionalized thiohydantoins compared to conventional protocols.

New 5-substituted hydantoins (III) and (IV) and symmetrical twin-drug type hydantoin derivatives (VII) are synthesized.

An efficient one-pot, two-step sequence starting from azide derivatives is described: first, formation of iminophosphoranes (Staudinger reaction) and condensation with carbon disulfide to form nonisolated isothiocyanates; then, condensation with α-amino esters to provide new N-3-substituted 2-thiohydantoins.

A rapid and highly efficient synthesis of 5-substituted hydantoin derivatives is achieved by three-component condensation of carbonyl compounds with KCN and (NH4)2CO3 under ultrasound irradiation conditions.

(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.

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

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.

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.

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.