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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.

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.

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.

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.

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.

A B S T R A C T A facile and rapid method for the one-pot synthesis of 5,5-disubstituted hydantoins in the presence of magnetic Fe3O4 nanoparticles has been developed. The multicomponent reactions of carbonyl compounds (aldehydes and ketones), potassium cyanide and ammonium carbonate were carried out under solvent-free conditions to obtain various hydantoin derivatives. The magnetic catalyst could be readily separated by an external magnet from the reaction mixture. This procedure has many advantages, such as the use of a reusable magnetic catalyst, high yields, short reaction times, simplicity and very easiness with implementing the methodology.

A short and efficient synthesis of (Z)-2-substituted-5-(4-((2-substitued-5-oxoimidazolidin-4-ylidene)methyl)benzamido)benzoic acid derivatives (8a–g) as potential type of FabH inhibitors is described. Their structures were confirmed by MS, NOE and 1H NMR.

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 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.

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.

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.

The characteristic vibrations ( ν CO and ν CC ) of a large number of hydantoin derivatives are reported. Especially the very fine correlations ν CO (sym) versus ν CO (asym) ( r 2 =0.985) but also successful correlations of the vibration wave numbers to HAMMETT's substituent constants and some other experimental parameters (p K s , OxPot, RedPot) as well, corroborate reassignments of previously obtained results [Monatsh. Chem. 92 (1961) 361] and prove the doublet obtained in the region of the CO stretching vibrations to be the symmetrical and anti -symmetrical vibrational modes of a mechanically coupled system of two quasi -symmetrical CO bonds.

The enantioseparation of eighteen new chiral hydantoin derivatives was studied on three different polysaccharide type chiral stationary phases (CSP) Chiralpak AD, Chiralcel OD and Chiralcel OJ in the normal-phase HPLC mode. Chiralpak AD material exhibited the most universal chiral resolving ability and allowed the enantioseparation of 17 out of 18 compounds followed by Chiralcel OD (10 enantioseparations of 12 tested compounds) and Chiralcel OJ (eight enantioseparation from 13 tested analytes). Some complementary separations were observed and all of 18 compounds could be resolved at least with one of the three chiral CSP under the conditions of this study. With regard to the structure of the analytes, bulky electron rich substituents at C5 of the hydantoin nucleus appear to favor stereoselective interactions.

A cascade of hydantoinase, N -carbamoylase and hydantoinracemase can be used for the production of natural and unnatural chiral d - and l -amino acids from chemically synthesized hydantoin derivatives. Potentially, 100% conversion and 100% optically pure amino acids can be obtained at the same time if racemic substrates are used. Recent research activities concentrate on newly isolated or improved enzymes and include directed evolution techniques, structure elucidation, studies of fusion proteins and the use of specially designed whole cell biocatalysts.

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.

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

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.

The infrared spectra in the region of fundamental CO stretching vibrations in methylenchloride were measured for nine 1,3-bis-substituted-5,5-dimethylhydantoins. The arithmetic means of wave numbers of symmetric and antysymmetric CO stretching vibrations are correlated with Taft's inductive σ* substituent constants. The mechanism of the transmission of substituent effects in hydantoin systems is discussed.

A total synthesis of (+)-hydantocidin 1, a new class of ribofuranose derivative exhibiting herbicidal activity, is reported. The spiro-hydantoin ring at the anomeric position of D -ribofuranose was constructed from substituted hydantoin derivatives 6, 7, and 12 through acid and base-promoted cyclization methods.

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.

The first of several conditions to be given the name of myokymia was the rare syndrome described by Schultze (1895) in which continuous, slow, undulating, muscular contractions are associated with a type of muscular spasm superficially resembling myotonia. A further case of this type is described. The clinical and electromyographic features are characteristic and the symptoms can be controlled by treatment with hydantoin derivatives.