Ring-Closure on the Rocks in a Prebiotic Environment.

Ring-closure is a key step in current pyrimidine anabolism and one may wonder whether cyclisation reactions could be promoted in the geochemical context at the origins of life, i. e. with the help of minerals. Various prebiotic minerals were tested in this work, including silica, carbonates, microporous minerals. In particular, the role of zinc ions supported on minerals was investigated in view of its presence in the catalytic site of cyclic amidohydrolase enzymes. Based on in situ (TGA: ThermoGravimetric Analysis, ATR-IR: Attenuated Total Reflectance-InfraRed) and ex situ (1 H NMR- Nuclear Magnetic Resonance) characterisations, we identified the products of thermal activation of NCA (N-carbamoyl-aspartic acid) in wetting-and-drying scenarios on the surface of minerals. NCA can cyclize extensively only on some surfaces, with the predominant product being 5-carboxymethylhydantoin (Hy) rather than dihydroorotate (DHO), while there is a competition with hydrolysis on others. Replacing the enzymes with heterogeneous catalysts also works with other reactions catalysed by enzymes of the cyclic amidohydrolases family. The role of the hydrophilicity/hydrophobicity of minerals as well as the regioselectivity of the cyclisation (5-carboxymethylhydantoin versus dihydroorotate) are examined.

Synthesis and Conformational Analysis of Hydantoin-Based Universal Peptidomimetics.

The synthesis of a collection of enantiomerically pure, systematically substituted hydantoins as structural privileged universal mimetic scaffolds is presented. It relies on a chemoselective condensation/cyclization domino process between isocyanates of quaternary or unsubstituted α-amino esters and N-alkyl aspartic acid diesters followed by standard hydrolysis/coupling reactions with amines, using liquid-liquid acid/base extraction protocols for the purification of the intermediates. Besides the nature of the α carbon on the isocyanate moiety, either a quaternary carbon or a more flexible methylene group, conformational studies in silico (molecular modeling), in solution (NMR, circular dichroism (CD), Fourier transform infrared (FTIR)), and in solid state (X-ray) showed that the presented hydantoin-based peptidomimetics are able to project their substituents in positions superimposable to the side chains of common protein secondary structures such as α-helix and ß-turn, being the open α-helix conformation slightly favorable according to molecular modeling, while the closed ß-turn conformation preferred in solution and in solid state.

Benzenesulfonamides Incorporating Hydantoin Moieties Effectively Inhibit Eukaryoticand Human Carbonic Anhydrases.

A series of novel 1-(4-benzenesulfonamide)-3-alkyl/benzyl-hydantoin derivatives were synthesized and evaluated for the inhibition of eukaryotic and human carbonic anhydrases (CAs, EC 4.2.1.1). The prepared compounds were screened for their hCA inhibitory activities against three cytosolic isoforms as well as two ß-CAs from fungal pathogens. The best inhibition was observed against hCA II and VII as well as Candida glabrata enzyme CgNce103. hCA I and Malassezia globosa MgCA enzymes were, on the other hand, less effectively inhibited by these compounds. The inhibitory potency of these compounds against CAs was found to be dependent on the electronic and steric effects of substituent groups on the N3-position of the hydantoin ring, which included alkyl, alkenyl and substituted benzyl moieties. The interesting results against CgNce103 make the compounds of interest for investigations in vivo as potential antifungals.

Insights into the 5-Carboxamido-5-Formamido-2-Iminohydantoin Structural Isomerization Equilibria.

Exposure of DNA to oxidants results in modification of the electron-rich guanine heterocycle including formation of the mutagenic 5-carboxamido-5-formamido-2-iminohydantoin (2Ih) lesion. Previously thought to exist solely as a pair of diastereomers, we found under biologically relevant conditions that 2Ih reversibly closes to a formerly hypothetical intermediate and opens into a newly discovered regioisomer. In a nucleoside model, only ∼80% of 2Ih existed as the structure studied over the last 20 years with significant isomeric products persisting in buffered aqueous solution.

3-Imino derivative-sulfahydantoins: Synthesis, in vitro antibacterial and cytotoxic activities and their DNA interactions.

Sulfahydantoins are five-membered rings found in the structure of chemicals that exhibit antibacterial, anti-inflammatory, and anticonvulsant properties. They also activate serine protease enzymes that catalyze the hydrolysis of peptide bonds. Five 3-imino sulfahydantoin compounds were synthesized by using Strecker synthesis reaction with minor modifications. We used reflux of various aldehydes with excess sulfamide in 85% methanol in the presence of sodium cyanide. The spectroscopic properties of these compounds were studied in detail. Antibacterial activities of all synthesized new compounds against four Gram-positive (Staphylococcus aureus, Bacillus cereus, Bacillus subtilis, Streptococcus mutans) and four Gram-negative (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella Enteritidis) bacteria were investigated by disc diffusion and microdilution method. pBR322 plasmid DNA binding abilities of compounds were investigated in vitro by agarose gel electrophoresis. In addition, the cytotoxic activities of the compounds against the human malignant pleural mesothelioma (SPC212) cell line were determined by the MTT method. The remarkable result in this study is that the synthesized compounds, especially 4b, 4d, and 4e, have significant biological activities. It has been demonstrated that these compounds, which cause DNA damage, also have an important antibacterial effect on both Gram-negative and Gram-positive bacteria when results compared with the control group antibiotics. Compound 4e exhibited the highest antibacterial potency against Streptococcus mutans (24.33 ± 0.57) from Gram-positive bacteria and Pseudomonas aeruginosa (24.66 ± 1.15) from Gram-negative bacteria. At the same time, MTT results determined that compounds 4b, 4d, and 4e showed cytotoxic activity against the SPC212 cells. In particular, compound 4b had a high cytotoxic effect, and the IC50 value was determined as 6.25 µM.

Hemimycalins C-E; Cytotoxic and Antimicrobial Alkaloids with Hydantoin and 2-Iminoimidazolidin-4-one Backbones from the Red Sea Marine Sponge Hemimycale sp.

In the course of our continuing efforts to identify bioactive secondary metabolites from Red Sea marine sponges, we have investigated the sponge Hemimycale sp. The cytotoxic fraction of the organic extract of the sponge afforded three new compounds, hemimycalins C-E (1-3). Their structural assignments were obtained via analyses of their one- and two-dimensional NMR spectra and HRESI mass spectrometry. Hemimycalin C was found to differ from the reported hydantoin compounds in the configuration of the olefinic moiety at C-5-C-6, while hemimycalins D and E were found to contain an 2-iminoimidazolidin-4-one moiety instead of the hydantoin moiety in previously reported compounds from the sponge. Hemimycalins C-E showed significant antimicrobial activity against Escherichia coli and Candida albicans and cytotoxic effects against colorectal carcinoma (HCT 116) and the triple-negative breast cancer (MDA-MB-231) cells.

The Bucherer-Bergs Multicomponent Synthesis of Hydantoins-Excellence in Simplicity.

Hydantoins and their hybrids with other molecules represent a very important group of heterocycles because they exhibit diverse biological and pharmacological activities in medicinal and agrochemical applications. They also serve as key precursors in the chemical or enzymatic synthesis of significant nonnatural α-amino acids and their conjugates with medical potential. This review provides a comprehensive treatment of the synthesis of hydantoins via the Bucherer-Bergs reaction including the Hoyer modification but limited to free carbonyl compounds or carbonyl compounds protected as acetals (ketals) and cyanohydrins used as starting reaction components. In this respect, the Bucherer-Bergs reaction provides an efficient and simple method in the synthesis of important natural products as well as for the preparation of new organic compounds applicable as potential therapeutics. The scope and limitations, as well as a comparison with some other methods for preparing hydantoins, are also discussed.

Direct N1-Selective Alkylation of Hydantoins Using Potassium Bases.

Hydantoins, including the antiepileptic drug phenytoin, contain an amide nitrogen and an imide nitrogen, both of which can be alkylated. However, due to the higher acidity of its proton, N3 can be more easily alkylated than N1 under basic conditions. In this study, we explored methods for direct N1-selective methylation of phenytoin and found that conditions using potassium bases [potassium tert-butoxide (tBuOK) and potassium hexamethyldisilazide (KHMDS)] in tetrahydrofuran (THF) gave N1-monomethylated phenytoin in good yield. The applicable scope of this reaction system was found to include various hydantoins and alkyl halides. To explore the function of methylated hydantoins, the effects of a series of methylated phenytoins on P-glycoprotein were examined, but none of methylated products showed inhibitory activity toward rhodamine 123 efflux by P-glycoprotein.

Synthesis of thia- and thioxo-tetraazaspiro[4.4]nonenones from nitrile imines and arylidenethiohydantoins.

5-Arylidene-1-methyl-2-thiohydantoins undergo [3+2]-cycloaddition reaction with nitrile imines, generated in situ from hydrazonyl chlorides, at C=C and C=S dipolarophiles in the thiohydantoin moiety to afford thioxo-tetraazaspiro[4.4]nonenones and thia-tetraazaspiro[4.4]nonenones in moderate to good yields. The stereochemistry of these spiroheterocycles has been confirmed by X-ray diffraction studies.

Design, Synthesis, Characterization, and Biological Activities of Novel Spirooxindole Analogues Containing Hydantoin, Thiohydantoin, Urea, and Thiourea Moieties.

On the basis of the scaffolds widely used in drug design, a series of novel spirooxindole derivatives containing hydantoin, thiohydantoin, urea, and thiourea moieties have been designed, synthesized, characterized, and first evaluated for their biological activities. The diastereoselectivity mechanism is proposed, and the systematic conformational analysis is performed. The bioassay results show that the target compounds possess moderate to good antiviral activities against tobacco mosaic virus (TMV), among which compound 22 shows the highest antiviral activity in vitro as well as inactivation, curative, and protection activities in vivo (45 ± 1, 47 ± 3, 50 ± 1, and 51 ± 1%, 500 mg/L, respectively), higher than ribavirin (38 ± 1, 36 ± 1, 38 ± 1, and 36 ± 1%, 500 mg/L, respectively). Thus, compound 22 is a promising candidate for anti-TMV development. Most of these compounds show broad-spectrum fungicidal activities against 14 kinds of phytopathogenic fungi and selective fungicidal activities against Physalospora piricola, Sclerotinia sclerotiorum, and Rhizoctonia cerealis. Additionally, some of these compounds exhibit insecticidal activity against Culex pipiens pallens, Mythimna separata, Helicoverpa armigera, and Pyrausta nubilalis. Compound 17 exhibits the highest larvicidal activity (LC50 was 0.32 mg/L) against C. pipiens pallens.

Axially chiral hemiaminals from nonracemic α-amino acid derivatives (thiohydantoins): Synthesis and isomer identification.

Stable, nonracemic axially chiral hemiaminals (O,N-hemiacetals) have been synthesized stereoselectively from lithium aluminum hydride (LiAlH4 ) reductions of nonracemic 5-methyl- and 5-isopropyl-3-(o-aryl)-2-thioydantoins in tetrahydrofuran (THF) at room temperature in 10 min. Predominantly S-configured hemiaminals at C-4 of the heterocyclic ring were produced from the S-configured thiohydantoins at C-5 (by 80% when the C5 substituent is methyl and by 97% when it is isopropyl). The configuration at C-5 was retained during the reduction reaction. The stereochemical outcome of the axially chiral hemiaminals resulted from their conformational preferences.

N-Halamine Hydantoin-Containing Chitosan: Synthesis, Characterization, Thermal and Photolytic Stability Studies.

Current demand for new protective materials ensuring sterility is systematically growing. The purpose of this work was the synthesis of the biocidal N-halamine hydantoin-containing chitosan (CS-CMH-Cl) and characterization of its properties. The functionalization of the chitosan by 5-hydantoinacetic acid substitution leads to obtaining the CS-CMH polymer, which was chlorinated in next step to transform N-H into N-Cl bonds. In this study, the possibility of forming two biocidal N-Cl bonds in hydantoin ring, grafted onto chitosan chains, was proved. The structure and stability of the prepared material was confirmed by spectroscopic (FTIR, NMR, colorimetric test) and microscopic analyses (SEM, AFM). Surface properties were investigated based on contact-angle measurements. In addition, the thermal and photochemical stability of the obtained samples were determined as functional features, determining the range of potential use. It was found that both modified chitosan polymers (CS-CMH and CS-CMH-Cl) were characterized by the smaller thermal stability and more hydrophilic and rougher surface than unmodified CS. Photooxidative degradation of the obtained materials was observed mainly on the sample surface. After irradiation, the surfaces became more hydrophilic-especially in the case of the CS-CMH-Cl-which is advantageous from the point of view of the antibacterial properties. Antibacterial tests against S. aureus and E. coli confirmed the antibacterial activities of received CS-CMH-Cl material.

Phenylpiperazine 5,5-Dimethylhydantoin Derivatives as First Synthetic Inhibitors of Msr(A) Efflux Pump in Staphylococcus epidermidis.

Herein, 15 phenylpiperazine 3-benzyl-5,5-dimethylhydantoin derivatives (1-15) were screened for modulatory activity towards Msr(A) efflux pump present in S. epidermidis bacteria. Synthesis, crystallographic analysis, biological studies in vitro and structure-activity relationship (SAR) analysis were performed. The efflux pump inhibitory (EPI) potency was determined by employing ethidium bromide accumulation assay in both Msr(A) efflux pump overexpressed (K/14/1345) and deficient (ATCC 12228) S. epidermidis strains. The series of compounds was also evaluated for the capacity to reduce the resistance of K/14/1345 strain to erythromycin, a known substrate of Msr(A). The study identified five strong modulators for Msr(A) in S. epidermidis. The 2,4-dichlorobenzyl-hydantoin derivative 9 was found as the most potent EPI, inhibiting the efflux activity in K/14/1345 at a concentration as low as 15.63 µM. Crystallography-supported SAR analysis indicated structural properties that may be responsible for the activity found. This study identified the first synthetic compounds able to inhibit Msr(A) efflux pump transporter in S. epidermidis. Thus, the hydantoin-derived molecules found can be an attractive group in search for antibiotic adjuvants acting via Msr(A) transporter.

Structural basis for the stabilization of amyloidogenic immunoglobulin light chains by hydantoins.

Misfolding and aggregation of immunoglobulin light chains (LCs) leads to the degeneration of post-mitotic tissue in the disease immunoglobulin LC amyloidosis (AL). We previously reported the discovery of small molecule kinetic stabilizers of the native dimeric structure of full-length LCs, which slow or stop the LC aggregation cascade at the outset. A predominant structural category of kinetic stabilizers emerging from the high-throughput screen are coumarins substituted at the 7-position, which bind at the interface between the two variable domains of the light chain dimer. Here, we report the binding mode of another, more polar, LC kinetic stabilizer chemotype, 3,5-substituted hydantoins. Computational docking, solution nuclear magnetic resonance experiments, and x-ray crystallography show that the aromatic substructure emerging from the hydantoin 3-position occupies the same LC binding site as the coumarin ring. Notably, the hydantoin ring extends beyond the binding site mapped out by the coumarin hits. The hydantoin ring makes hydrogen bonds with both LC monomers simultaneously. The alkyl substructure at the hydantoin 5-position partially occupies a novel binding pocket proximal to the pocket occupied by the coumarin substructure. Overall, the hydantoin structural data suggest that a larger area of the LC variable-domain-variable-domain dimer interface is amenable to small molecule binding than previously demonstrated, which should facilitate development of more potent full-length LC kinetic stabilizers.

Self-Assembly and Biorecognition of a Spirohydantoin Derived from α-Tetralone: Interplay between Chirality and Intermolecular Interactions.

A racemic spirohydantoin derivative with two aromatic substituents, a tetralin and a 4-methoxybenzyl unit, was synthesized and its crystal structure was determined. To define the relationship between molecular stereochemistry and spatial association modes, development of the crystal packing was analyzed through cooperativity of intermolecular interactions. Homo and heterochiral dimeric motifs were stabilized by intermolecular N-H⋅⋅⋅O, C-H⋅⋅⋅O, C-H⋅⋅⋅π interactions and parallel interactions at large offsets (PILO), thus forming alternating double layers. The greatest contribution to the total stabilization came from a motif of opposite enantiomers linked by N-H⋅⋅⋅O bonds (interaction energy=-13.72 kcal/mol), followed by a homochiral motif where the 4-methoxybenzyl units allowed C-H⋅⋅⋅π, C-H⋅⋅⋅O interactions and PILO (interaction energy=-11.56 kcal/mol). The number of the contact fragments in the environment of the tetralin unit was larger, but the 4-methoxybenzyl unit had greater contribution to the total stabilization. The statistical analysis of the data from the Cambridge Structural Database (CSD) showed that this is a general trend. The compound is a potential inhibitor of kinase enzymes and antigen protein-coupled receptors. A correlation between the docking study and the results of the CSD analysis can be drawn. Due to a greater flexibility, the 4-methoxybenzyl unit is more adaptable for interactions with the biological targets than the tetralin unit.

Discovery of phenylselenoether-hydantoin hybrids as ABCB1 efflux pump modulating agents with cytotoxic and antiproliferative actions in resistant T-lymphoma.

Multidrug resistance (MDR) in cancer cells is a crucial aspect to consider for a successful cancer therapy. P-gp/ABCB1, a member of ABC transporters, is involved in the main tumour MDR mechanism, responsible for the efflux of drugs and cytotoxic substances. Herein, we describe a discovery of potent selenium-containing ABCB1 MDR efflux pump modulators with promising anticancer activity. On three groups of selenoethers comprehensive studies in terms of design, synthesis, and biological assays, including an insight into cellular mechanisms of anticancer action as well as an ADMET-screening in vitro were performed, followed by in-depth SAR analysis. Among the investigated new phenylselenoether hybrids, four compounds showed significant cytotoxic and anti-proliferative effects, in particular, in resistant cancer cells. Hydantoin derivatives (5-7) were significantly more effective than the reference inhibitor verapamil (up to 2.6-fold at a 10-fold lower concentration) modulating ABCB1-efflux pump, also possessing a good drug-drug interaction profile. The best compound (6) was further evaluated in human JURKAT T-lymphocytic cancer cells for its impact on cell proliferation rate. Mechanistically, the expression of cyclin D1, an enhancer of the cell cycle, decreases, while p53, an inhibitor of cell proliferation, was up-regulated upon the treatment with compound 6 alone or in combination with the chemotherapeutic agent doxorubicin. In summary, a new chemical space of highly active selenium-containing anticancer agents has been discovered, with a new lead compound 6 that warrants more in-depth biological evaluation and further pharmacomodulation.

Residue behavior and removal of iprodione in garlic, green garlic, and garlic shoot.

BACKGROUND: Iprodione is considered to be an endocrine-disturbing pesticide, which could harm consumers. The garlic crop has three edible parts: the garlic, the green garlic, and the garlic shoot, which correspond to different stages of its growth. In this study, iprodione residue dissipation and distribution in these three edible parts were investigated, and dietary risk was evaluated. RESULTS: Iprodione residues were present in these samples in the following order: green garlic > garlic shoot > > garlic. The dissipation of iprodione in green garlic was slow with a half-life of 5.82-19.25 days. A very high RQchronic value of 207.35-407.30% suggested that the residual iprodione in green garlic had an unacceptable level of risk. Iprodione residue was significantly eliminated (59-90%) by an alkaline solution. The order for removing iprodione by soaking was the alkaline solutions (0.5% and 2% NaHCO3 ) > the acidic solutions (5% and 10% of vinegar) ≈ the neutral solutions (the 1% and 2% of table salt) > tap water. Processing factors (PFs) were <1, indicating that processing could decrease the iprodione residue level. CONCLUSION: This work could contribute to establishing maximum residue limits (MRLs) for iprodione in garlic, green garlic, and garlic shoots, and could provide guidance on the safe and appropriate use of iprodione in the garlic crop. © 2020 Society of Chemical Industry.

RNA polymerase II stalls on oxidative DNA damage via a torsion-latch mechanism involving lone pair-π and CH-π interactions.

Oxidation of guanine generates several types of DNA lesions, such as 8-oxoguanine (8OG), 5-guanidinohydantoin (Gh), and spiroiminodihydantoin (Sp). These guanine-derived oxidative DNA lesions interfere with both replication and transcription. However, the molecular mechanism of transcription processing of Gh and Sp remains unknown. In this study, by combining biochemical and structural analysis, we revealed distinct transcriptional processing of these chemically related oxidized lesions: 8OG allows both error-free and error-prone bypass, whereas Gh or Sp causes strong stalling and only allows slow error-prone incorporation of purines. Our structural studies provide snapshots of how polymerase II (Pol II) is stalled by a nonbulky Gh lesion in a stepwise manner, including the initial lesion encounter, ATP binding, ATP incorporation, jammed translocation, and arrested states. We show that while Gh can form hydrogen bonds with adenosine monophosphate (AMP) during incorporation, this base pair hydrogen bonding is not sufficient to hold an ATP substrate in the addition site and is not stable during Pol II translocation after the chemistry step. Intriguingly, we reveal a unique structural reconfiguration of the Gh lesion in which the hydantoin ring rotates ∼90° and is perpendicular to the upstream base pair planes. The perpendicular hydantoin ring of Gh is stabilized by noncanonical lone pair-π and CH-π interactions, as well as hydrogen bonds. As a result, the Gh lesion, as a functional mimic of a 1,2-intrastrand crosslink, occupies canonical -1 and +1 template positions and compromises the loading of the downstream template base. Furthermore, we suggest Gh and Sp lesions are potential targets of transcription-coupled repair.

Optimization of Hydantoins as Potent Antimycobacterial Decaprenylphosphoryl-ß-d-Ribose Oxidase (DprE1) Inhibitors.

In search of novel drugs against tuberculosis, we previously discovered and profiled a novel hydantoin-based family that demonstrated highly promising in vitro potency against Mycobacterium. tuberculosis. The compounds were found to be noncovalent inhibitors of DprE1, a subunit of decaprenylphosphoryl-ß-d-ribose-2'-epimerase. This protein, localized in the periplasmic space of the mycobacterial cell wall, was shown to be an essential and vulnerable antimycobacterial drug target. Here, we report the further SAR exploration of this chemical family through more than 80 new analogues. Among these, the most active representatives combined submicromolar cellular potency and nanomolar target affinity with balanced physicochemical properties and low human cytotoxicity. Moreover, we demonstrate in vivo activity in an acute Mtb infection model and provide further proof of DprE1 being the target of the hydantoins. Overall, the hydantoin family of DprE1 inhibitors represents a promising noncovalent lead series for the discovery of novel antituberculosis agents.