Search

A flexible docking of a series of heteroaryl compounds to the binding site of a model of human 5-HT1A/2A receptor was exercised using GLIDE docking methods. The resultant docking scores were used to correlate the in vivo affinity data. The GLIDE docking algorithm when used with a homology model of 5HT1A/2A was based on β2- adrenergic receptor template. The influence of structure and hydrophobic properties of aryl moiety on binding affinities was discussed and a model for ligand binding in the hydrophobic part of the binding site was proposed.

5-Spirofluorenehydantoin derivatives show efflux modulating, cytotoxic and antiproliferative effects in sensitive and resistant mouse T-lymphoma cells. In order to extend the knowledge available about the pharmacophoric features responsible for the glycoprotein P (P-gp) inhibitory properties of arylpiperazine derivatives of 3-methyl-5-spirofluorenehydantoin, we have performed crystal structure analyses for 1-[3-(3′-methyl-2′,4′-dioxospiro[fluorene-9,5′-imidazolidin]-1′-yl)propyl]-4-phenylpiperazine-1,4-diium dichloride monohydrate, C29H32N4O2 2+·2Cl−·H2O (1), 3′-methyl-1′-{3-[4-(4-nitrophenyl)piperazin-1-yl]propyl}spiro[fluorene-9,5′-imidazolidine]-2′,4′-dione, C29H29N5O4·H2O (2), 3′-methyl-1′-{5-[4-(4-nitrophenyl)piperazin-1-yl]pentyl}spiro[fluorene-9,5′-imidazolidine]-2′,4′-dione, C31H33N5O4 (3), and 1-benzyl-4-[5-(3′-methyl-2′,4′-dioxospiro[fluorene-9,5′-imidazolidin]-1′-yl)pentyl]piperazine-1,4-diium dichloride 0.613-hydrate, C32H38N4O2 2+·2Cl−·0.613H2O (4). Structure 3 is anhydrous but the other three structures crystallize with water present. The investigated compounds crystallize in the monoclinic crystal system, with the space group P21/n for 1 and 3, and P21/c for 2 and 4. The cations of salts 1 and 4 are doubly protonated, with the protons located on the N atoms of the piperazine rings. The packing of 1 and 4 in the crystals is dominated by intermolecular N—H...Cl and O—H...Cl hydrogen bonds. In the crystal structure of 2, the intermolecular interactions are dominated by O—H...O and O—H...N hydrogen bonds, while in 3, which is lacking in classic hydrogen-bond donors, it is C—H...O contacts that dominate. Additionally, we have performed induced-fit docking studies for the investigated compounds docked to the P-gp human homology model.

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]

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. Keywords: Hydantoin derivatives, Breast cancer cell line MDA-MB-231, Proliferation, Apoptosis, Cell motility, Nitric oxide

This study aimed to assess two novel 5-arylideneimidazolidine-2,4-dione (hydantoin) derivatives (JH3 and JH10) demonstrating photoprotective activity using the reconstructed human skin model EpiskinTM. The skin permeability, irritation, and phototoxicity of the compounds was evaluated in vitro. Moreover, the in vitro genotoxicity and human metabolism of both compounds was studied. For skin permeation and irritation experiments, the test compounds were incorporated into a formulation. It was shown that JH3 and JH10 display no skin irritation and no phototoxicity. Both compounds did not markedly enhance the frequency of micronuclei in CHO-K1 cells in the micronucleus assay. Preliminary in vitro studies with liver microsomes demonstrated that hydrolysis appears to constitute their important metabolic pathway. EpiskinTM permeability experiments showed that JH3 permeability was lower than or close to currently used UV filters, whereas JH10 had the potential to permeate the skin. Therefore, a restriction of this compound permeability should be obtained by choosing the right vehicle or by optimizing it, which should be addressed in future studies.

Alzheimer’s disease (AD) is the most common dementia in late life memory related issues. It is estimated that worldwide 46.8 million people suffer from dementia. The hypoxia inducible factor (HIF) ...

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 effective aza-Mannich reaction between olefinic rhodanines/hydantoins and N-Boc aminals catalyzed by Bronsted acid has been developed. Multifunctional rhodanine/hydantoin derivatives were obtained in 71–86% yields and an up to 95/5 Z/E ratio under mild conditions.

Hydantoins and their sulfur containing analogues, thiohydantoins, are an important and interesting moiety. They represent a big group of structurally diverse compounds with intriguing physical, chemical and biological properties, which enabled them to be used in therapy, medicine in general, material science and industry. With the goal of broadening the set of potentially applicable hydantoin derivatives, we have synthesized a series of 2-thiohydantoins from vanillin and its derivatives, which themselves posses interesting biological properties. All compounds were fully characterized by NMR and IR spectroscopy. The compounds will be subjected to intensive biological screening to determine their biological properties and application opportunities.

We report an efficient synthetic strategy to diverse hydantoins and thiohydantoins involving a three-component reaction with the aid of deep eutectic solvent. Here, N,N'-dimethyl urea and N,N'-dimethyl thiourea play a dual role as reactant and reaction medium along with l-(+)-tartaric acid. The three-component reaction provides an easy access to 5-amino-1,3-dialkyl-substituted hydantoins and thiohydantoins in good yields.

A mild and efficient one-pot three-component and environmentally benign approach for the synthesis of a wide range of hydantoin annulated derivatives has been described. A multi-component reaction between a carbonyl compounds (ketone or aldehyde), potassium cyanide and ammonium carbonate (as cyanating agent and amine source, respectively leads to the formation of hydantoins. The proposed optimized reaction conditions ,i.e. solvent-free conditions under ambient temperature in the presence of low amount of ZnOnano-catalyst, were very efficient resulting in the formation of the desired products with good to excellent yields. Furthermore, the presented methodology is in accord with green chemistry principles.Keywords: Bucherer-Bergs; hydantoin derivatives; multicomponent reactions (MCRs); green chemistry.

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 new family of molecular photoswitches based on arylidenehydantoins is described together with their synthesis and photochemical and photophysical studies. A series of hydantoin derivatives have been prepared as single isomers using simple and versatile chemistry in good yields. Our studies show that the photostationary states of these compounds can be easily controlled by means of external factors, such as the light source or filters. Moreover, the detailed investigations proved that these switches are efficient (i.e., they make efficient use of the light energy, are high fatigue resistant, and are very photostable). In some cases, the switches can be completely turned on/off, a desirable feature for specific applications. A series of theoretical calculations have also been carried out to understand the photoisomerization mechanism at the molecular level.

Generally, synthesis of hydantoin derivatives involve use of carbonyl compounds which in turn require multistep synthesis. Here, we report a new approach to assemble spirohydantoins via [2+2+2] cyclotrimerization reaction using commercially available, inexpensive hydantoin as a starting material. (C) 2018 Elsevier Ltd. All rights reserved.

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.

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.

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.

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.

2-(Alkyl-1-yl)-1 H -imidazol-5(4 H) -ones 5a–n were synthesized via nucleophilic substitution of the methylsulfanyl group of the corresponding 2-(methylthio)-1 H -imidazol-5(4 H )-ones 3a–c with suitably substituted secondary amines. The starting 2-thioxo- imidazolidin-4-ones 2a , 2b were prepared by condensation of thiohydantoin and benzo[ b ]-thiophene-3-carbaldehyde or benzofuran-3-carbaldehyde under microwave irracdiation (MW) conditions. 2-Methylthio derivatives 3a–c were prepared by treatment of 2a–b with methyl iodide in the presence of aqueous sodium hydroxide. Keywords: MW assisted synthesis; hydantoin; arylidene-4 H -imidazoles 1. Introduction Hydantoin derivatives have achieved considerable success as anticonvulsant agents [1]. The nucleosides of several 5-arylidene-3-arylhydantoins and 2-thiohydantoins show potent activity against human immunodeficiency virus (HIV) [2] and the leukemia subpanel [3]. A recent study showed that S -glucosylated hydantoins (Figure 1) act against herpes simplex virus, type 1 (HSV-1) and type 2 (HSV-2) in Vero cells [4]. A further study reported that thiazolidinediones (TZDs), which are known to have potent enhancing effects on insulin sensitivity, have been developed for the treatment of noninsulin-dependent diabetes mellitus [5,6].

In this study 18 hydantoin derivatives were investigated by means of reversed-phase LC on C-18 stationary phase and methanol–water eluent. Quantitative structure–retention relationship study has been applied in order to understand factors that affect the chromatographic behavior which is closely correlated to the activity (ED50 values). A multiple linear regression procedure was used to model the relationships between molecular descriptors and retention of the hydantoin derivatives. The best quantitative structure–activity relationship (QSAR) models were further validated by a leave-one-out technique as well as by the calculation of statistical parameters for the established theoretical models. High agreement between experimental and predicted data obtained in the validation procedure indicated good quality of the derived QSAR models.

A reinvestigation of the Biltz synthesis of phenytoin was undertaken to selectively produce the hydantoin derivative instead of a mixture of the hydantoin and the glycoluryl derivative. A solution of this problem was found in carrying out the reaction in a two-phase system (n-butanol:water) and in the presence of a phase-transfer catalyst (poly(ethyleneglycol)600). In these conditions, a 87–93 yield of phenytoin can be obtained. Extension of this approach to the synthesis of other hydantoin derivatives was also found superior to one-phase conditions.

We have examined the reaction of hydantoin (=imidazolidine-2,4-dione) with (formylphenyl)boronic acids, where the addition of a boronic acid group is hoped to increase bioactivities. Addition of (2-formylphenyl)boronic acid to hydantoin gave an unexpected azaborine compound, which presumably arises by initial formation of the (phenylmethylidene)hydantoin, with subsequent loss of H2O to give the cyclized product. Reactions of (3-formylphenyl)- and (4-formylphenyl)boronic acids with hydantoin gave the corresponding [(Z)-phenylmethylidene]hydantoins in good-to-excellent yields. Attempts to use (3-formylthiophen-2-yl)boronic acid gave a product where the boronic acid group has been cleaved.

Summary The behavior of 5,5-disubstituted hydantoin derivatives has been studied using four chromatographic systems, two normal-phase (silica gel stationary phase with ethyl acetate–toluene and acetonitrile–toluene mobile phases) and two reversed-phase (RP-18 systems with methanol–water and acetonitrile–water mobile phases). The effect of the structures of the derivatives on their retention in both normal and reversed-phase modes was investigated by use of QSRR and molecular descriptors. By means of multiple linear regressions results were interpreted in terms of understandable and physically meaningful variables. Among six models proposed, the two best were selected and tested for prediction of retention – one for normal-phase chromatography (NPC) and the other for reversed-phase chromatography (RPC). The most informative properties in the best NPC model, with similar effects on retention, are log P and valence connectivity indices. The informative properties in the best RPC model were log P and molecular weight, but the statistics was much worse than for NPC. Cross-validation indicated the best models are reliable QSRR models.

Six new polyamides 5a-f containing flexible trimethylene segments in the main chain were synthesized through the direct polycondensation reaction of 1,3-bis(4-carboxy phenoxy) propane 3 with six derivatives of hydantoins 5a-f in a medium consisting of N-methyl-2-pyrrolidone, triphenyl phosphite, calcium chloride and pyridine. The polycondensation reaction produced a series of novel polyamides in high yield with inherent viscosities between 0.30-0.47 dL/g. The resulted polymers were fully characterized by means of FT-IR, 1H-NMR spectroscopy, elemental analyses, inherent viscosity, solubility tests and gel permeation chromatography (GPC). Thermal properties of these polymers were investigated by using thermal gravimetric analysis (TGA) and differential thermal gravimetry (DTG). The glass-transition temperatures of these polyamides were recorded between 130 and 155 oC by differential scanning calorimetry (DSC), and the 5% weight loss temperatures were ranging from 325 to 415 oC under nitrogen. 1,3-bis(4-Carboxy phenoxy) propane 3 was prepared from the reaction of 4-hydroxy benzoic acid 1 with 1,3-dibromo propane 2 in the presence of NaOH solution.

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 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).

The title compound, C13H13N2O3, a hydantoin derivative, crystallized with two molecules (AandB) in an asymmetric unit. In moleculeA, the imidazolidine ring is twisted about the C—N bond involving the spiro C atom, while in moleculeBthis ring is flat (r.m.s. deviation = 0.010 Å). The pyran rings in both molecules have distorted half-chair conformations. The mean plane of the imidazolidine ring is inclined to the aromatic ring of the chroman unit by 79.71 (11)° in moleculeAand 82.83 (12)° in moleculeB. In the crystal, pairs of N—H...O hydrogen bonds link the individual molecules to formA–AandB–Binversion dimers. The dimers are linkedviaN—H...O and C—H...O hydrogen bonds, forming sheets lying parallel to thebcplane,viz.(011). Within the sheets, theAandBmolecules are linked by C—H...π interactions.

Cancer is the major health problem affecting the mankind of today. Most of the drugs used in traditional chemotherapy are very limited and the discovery of novel, more active, more selective and less toxic ones is still very intensive. A chemometric approach was applied in the study of antiproliferative activity against human colon cancer and breast cancer as well as in the study of lipophilicity of 3-(4-substituted benzyl)-5-ethyl-5-phenyl- and 3-(4-substituted benzyl)- 5,5-diphenylhydantoins. Hierarchical clustering analysis (HCA) shows that the investigated hydantoins have higher antiproliferative activity against human breast cancer cells than against human colon cancer cells. However, some hydantoins at the highest applied concentration reverse antiproliferative effect, higher against the human colon cancer cells and lower against human breast cancer cells. Principal component analysis (PCA) gives better insight into the activity of hydantoins related to their structural changes. It distinguishes more active compounds from the less active ones according to various criteria. Generally, more lipophilic 5,5-diphenylhydantoins exhibit a higher antiproliferative activity comparing to less lipophilic 5-ethyl-5-phenylhydantoins. Also, a substituent attached to benzyl moieties affects the activity additionally. The activity is particularly pronounced for compounds with cyano, methyl, chloro and bromo group. Halogen substituent were superior in antiproliferative capacity particularly in the series of 5,5-diphenylhydantoins.

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.