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1.
J Enzyme Inhib Med Chem ; 39(1): 2335927, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38606915

RESUMO

A novel series of hydantoins incorporating phthalimides has been synthesised by condensation of activated phthalimides with 1-aminohydantoin and investigated for their inhibitory activity against a panel of human (h) carbonic anhydrase (CA, EC 4.2.1.1): the cytosolic isoforms hCA I, hCA II, and hCA VII, secreted isoform hCA VI, and the transmembrane hCA IX, by a stopped-flow CO2 hydrase assay. Although all newly developed compounds were totally inactive on hCA I and mainly ineffective towards hCA II, they generally exhibited moderate repressing effects on hCA VI, VII, and IX with KIs values in the submicromolar to micromolar ranges. The salts 3a and 3b, followed by derivative 5, displayed the best inhibitory activity of all the evaluated compounds and their binding mode was proposed in silico. These compounds can also be considered interesting starting points for the development of novel pharmacophores for this class of enzyme inhibitors.


Assuntos
Anidrases Carbônicas , Hidantoínas , Humanos , Anidrases Carbônicas/metabolismo , Anidrase Carbônica IX , Relação Estrutura-Atividade , Anidrase Carbônica I , Anidrase Carbônica II , Isoformas de Proteínas/metabolismo , Ftalimidas/farmacologia , Hidantoínas/farmacologia , Inibidores da Anidrase Carbônica/química , Estrutura Molecular
2.
Curr Opin Genet Dev ; 85: 102165, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38428317

RESUMO

B cells undergoing physiologically programmed or aberrant genomic alterations provide an opportune system to study the causes and consequences of genome mutagenesis. Activated B cells in germinal centers express activation-induced cytidine deaminase (AID) to accomplish physiological somatic hypermutation (SHM) of their antibody-encoding genes. In attempting to diversify their immunoglobulin (Ig) heavy- and light-chain genes, several B-cell clones successfully optimize their antigen-binding affinities. However, SHM can sometimes occur at non-Ig loci, causing genetic alternations that lay the foundation for lymphomagenesis, particularly diffuse large B-cell lymphoma. Thus, SHM acts as a double-edged sword, bestowing superb humoral immunity at the potential risk of initiating disease. We refer to off-target, non-Ig AID mutations - that are often but not always associated with disease - as aberrant SHM (aSHM). A key challenge in understanding SHM and aSHM is determining how AID targets and mutates specific DNA sequences in the Ig loci to generate antibody diversity and non-Ig genes to initiate lymphomagenesis. Herein, we discuss some current advances regarding the regulation of AID's DNA mutagenesis activity in B cells.


Assuntos
Genômica , Hidantoínas , Compostos de Mostarda Nitrogenada , Mutação
3.
Bioorg Chem ; 146: 107284, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38493640

RESUMO

Based on the well-established pharmacophoric features required for histone deacetylase (HDAC) inhibition, a novel series of easy-to-synthesize benzimidazole-linked (thio)hydantoin derivatives was designed and synthesized as HDAC6 inhibitors. All target compounds potently inhibited HDAC6 at nanomolar levels with compounds 2c, 2d, 4b and 4c (IC50s = 51.84-74.36 nM) being more potent than SAHA reference drug (IC50 = 91.73 nM). Additionally, the most potent derivatives were further assessed for their in vitro cytotoxic activity against two human leukemia cells. Hydantoin derivative 4c was equipotent/superior to SAHA against MOLT-4/CCRF-CEM leukemia cells, respectively and demonstrated safety profile better than that of SAHA against non-cancerous human cells. 4c was also screened against different HDAC isoforms. 4c was superior to SAHA against HDAC1. Cell-based assessment of 4c revealed a significant cell cycle arrest and apoptosis induction. Moreover, western blotting analysis showed increased levels of acetylated histone H3, histone H4 and α-tubulin in CCRF-CEM cells. Furthermore, docking study exposed the ability of title compounds to chelate Zn2+ located within HDAC6 active site. As well, in-silico evaluation of physicochemical properties showed that target compounds are promising candidates in terms of pharmacokinetic aspects.


Assuntos
Antineoplásicos , Hidantoínas , Leucemia , Humanos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/química , Relação Estrutura-Atividade , Hidantoínas/farmacologia , Proliferação de Células , Antineoplásicos/farmacologia , Antineoplásicos/química , Histona Desacetilases/metabolismo , Linhagem Celular Tumoral , Histonas/metabolismo , Leucemia/tratamento farmacológico , Zinco/metabolismo , Simulação de Acoplamento Molecular
4.
Bioorg Med Chem Lett ; 103: 129701, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38484804

RESUMO

Malaria, a devastating disease, has claimed numerous lives and caused considerable suffering, with young children and pregnant women being the most severely affected group. However, the emergence of multidrug-resistant strains of Plasmodium and the adverse side effects associated with existing antimalarial drugs underscore the urgent need for the development of novel, well-tolerated, and more efficient drugs to combat this global health threat. To address these challenges, six new hydantoins derivatives were synthesized and evaluated for their in vitro antiplasmodial activity. Notably, compound 2c exhibited excellent inhibitory activity against the tested Pf3D7 strain, with an IC50 value of 3.97 ± 0.01 nM, three-fold better than chloroquine. Following closely, compound 3b demonstrated an IC50 value of 27.52 ± 3.37 µM against the Pf3D7 strain in vitro. Additionally, all the hydantoins derivatives tested showed inactive against human MCR-5 cells, with an IC50 value exceeding 100 µM. In summary, the hydantoin derivative 2c emerges as a promising candidate for further exploration as an antiplasmodial compound.


Assuntos
Antimaláricos , Hidantoínas , Malária , Gravidez , Criança , Feminino , Humanos , Pré-Escolar , Plasmodium falciparum , Cloroquina/farmacologia , Malária/tratamento farmacológico , Hidantoínas/farmacologia
5.
J Med Chem ; 67(6): 4819-4832, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38470227

RESUMO

The inhibition of emopamil binding protein (EBP), a sterol isomerase within the cholesterol biosynthesis pathway, promotes oligodendrocyte formation, which has been proposed as a potential therapeutic approach for treating multiple sclerosis. Herein, we describe the discovery and optimization of brain-penetrant, orally bioavailable inhibitors of EBP. A structure-based drug design approach from literature compound 1 led to the discovery of a hydantoin-based scaffold, which provided balanced physicochemical properties and potency and an improved in vitro safety profile. The long half-lives of early hydantoin-based EBP inhibitors in rodents prompted an unconventional optimization strategy, focused on increasing metabolic turnover while maintaining potency and a brain-penetrant profile. The resulting EBP inhibitor 11 demonstrated strong in vivo target engagement in the brain, as illustrated by the accumulation of EBP substrate zymostenol after repeated dosing. Furthermore, compound 11 enhanced the formation of oligodendrocytes in human cortical organoids, providing additional support for our therapeutic hypothesis.


Assuntos
Encéfalo , Hidantoínas , Humanos , Oligodendroglia/metabolismo , Desenho de Fármacos , Hidantoínas/metabolismo
6.
Environ Sci Pollut Res Int ; 31(11): 17289-17298, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38340299

RESUMO

The present work explores the genotoxicity of the fungicides iprodione (IP) and tebuconazole (TB) using the Allium cepa assay as an in vivo biological model. Both short-term and long-term exposures were studied, revealing concentration- and time-dependent cytological and genotoxic effects. IP exhibited genotoxicity over a wider concentration range (5-50 µg/ml) and required 30 h of exposure, while TB showed genotoxicity at higher concentrations (10 and 30 µg/ml) within a 4-h exposure period. The study highlights the importance of assessing potential risks associated with fungicide exposure, including handling, disposal practices, and concerns regarding food residue. Moreover, the research underscores the genotoxic effects of IP and TB on plant cells and provides valuable insights into their concentration and time-response patterns.


Assuntos
Aminoimidazol Carboxamida/análogos & derivados , Fungicidas Industriais , Hidantoínas , Cebolas , Triazóis , Meristema , Fungicidas Industriais/toxicidade , Dano ao DNA , Raízes de Plantas , Aberrações Cromossômicas
7.
Ecotoxicol Environ Saf ; 270: 115911, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38181604

RESUMO

Iprodione is an effective and broad-spectrum fungicide commonly used for early disease control in fruit trees and vegetables. Due to rainfall, iprodione often finds its way into water bodies, posing toxicity risks to non-target organisms and potentially entering the human food chain. However, there is limited information available regarding the developmental toxicity of iprodione specifically on the liver in existing literature. In this study, we employed larval and adult zebrafish as models to investigate the toxicity of iprodione. Our findings revealed that iprodione exposure led to yolk sac edema and increased mortality in zebrafish. Notably, iprodione exhibited specific effects on zebrafish liver development. Additionally, zebrafish exposed to iprodione experienced an overload of reactive oxygen species, resulting in the upregulation of p53 gene expression. This, in turn, triggered hepatocyte apoptosis and disrupted carbohydrate/lipid metabolism as well as energy demand systems. These results demonstrated the substantial impact of iprodione on zebrafish liver development and function. Furthermore, the application of astaxanthin (an antioxidant) and p53 morpholino partially mitigated the liver toxicity caused by iprodione. To summarize, iprodione induces apoptosis through the upregulation of p53 mediated by oxidative stress signals, leading to liver toxicity in zebrafish. Our study highlights that exposure to iprodione can result in hepatotoxicity in zebrafish, and it may potentially pose toxicity risks to other aquatic organisms and even humans.


Assuntos
Aminoimidazol Carboxamida/análogos & derivados , Doença Hepática Induzida por Substâncias e Drogas , Hidantoínas , Peixe-Zebra , Animais , Humanos , Peixe-Zebra/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Estresse Oxidativo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Embrião não Mamífero/metabolismo , Apoptose
8.
Int J Pharm ; 651: 123779, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38181993

RESUMO

Prolonged and excessive use of biocides during the coronavirus disease era calls for incorporating new antiviral polymers that enhance the surface design and functionality for existing and potential future pandemics. Herein, we investigated previously unexplored polyamines with nucleophilic biguanide, guanidine, and hydantoin groups that all can be halogenated leading to high contents of oxidizing halogen that enables enhancement of the biocidal activity. Primary amino groups can be used to attach poly(N-vinylguanidine) (PVG) and poly(allylamine-co-4-aminopyridine-co-5-(4-hydroxybenzylidene)hydantoin) (PAH) as well as a broad-spectrum commercial biocide poly(hexamethylene biguanide) (PHMB) onto a solid support. Halogenation of polymer suspensions was conducted through in situ generation of excess hypobromous acid (HBrO) from bromine and sodium hydroxide or by sodium hypochlorite in aqueous solutions, resulting in N-halamines with high contents of active > N-Br or > N-Cl groups. The virucidal activity of the polymers against human respiratory coronavirus HCoV-229E increased dramatically with their halogenation. Brominated PHMB-Br showed activation activity value > 5 even at 1 mg/L, and complete virus inhibition was observed with either PHMB-Br or PAH-Br at 10 mg/mL. Brominated PVG-Br and PAH-Br possessed fungicidal activity against C. albicans, while PHMB was fungistatic. PHMB, PHMB-Br and PAH polymers demonstrated excellent bactericidal activity against the methicillin-resistant S. aureus and vancomycin-resistant E. faecium. Brominated polymers (PHMB-Br, PVG-Br, PAH-Br) were not toxic to the HeLa monolayers, indicating acceptable biocompatibility to cultured human cells. With these features, the N-halamine polymers of the present study are a worthwhile addition to the arsenal of biocides and are promising candidates for development of non-leaching coatings.


Assuntos
Desinfetantes , Hidantoínas , Staphylococcus aureus Resistente à Meticilina , Humanos , Hidantoínas/farmacologia , Guanidina , Polímeros/farmacologia , Desinfetantes/farmacologia , Biguanidas/farmacologia , Candida albicans
9.
J Colloid Interface Sci ; 657: 788-798, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38081113

RESUMO

HYPOTHESIS: Poly (vinyl alcohol) (PVA) cryogels can be functionalized with n-Halamines to confer biocidal features useful for their application as wound-dressing tools. Their efficacy can be boosted by stably embedding a polymeric bacterial food source (e.g., starch) in the gel matrix. The bioavailability of the food source lures bacteria inside the gel network via chemotactic mechanisms, promoting their contact with the biocidal functionalities and their consequent inactivation. EXPERIMENTS: The synthesis of a novel hydantoin-functionalized PVA (H-PVA-hyd) is proposed. The newly synthesized H-PVA-hyd polymer was introduced in the formulation of H-PVA-based cryogels. To promote the cryogelation of the systems we exploited phase-separation mechanisms employing either a PVA carrying residual acetate groups (L-PVA) or starch as phase-segregating components. The permanence of the biocidal functionality after swelling was investigated via proton nuclear magnetic resonance (1H NMR) and Fourier transform infrared (FT-IR) microscopy. The activated H-PVA-hyd cryogels have been tested against bacteria with amylolytic activity (Bacillus subtilis) and the outcomes were analyzed by direct observation via confocal laser scanning microscopy (CLSM). FINDINGS: The cryogels containing starch resulted in being the most effective (up to 90% bacterial killing), despite carrying a lower amount of hydantoin groups than their starch-free counterparts, suggesting that their improved efficacy relies on a "Trojan Horse" type of mechanism.


Assuntos
Hidantoínas , Amido , Amido/química , Álcool de Polivinil/química , Criogéis , Bacillus subtilis , Hidantoínas/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier , Géis , Polímeros , Etanol
10.
Molecules ; 28(21)2023 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-37959862

RESUMO

In a sustained search for novel potential drug candidates with multispectrum therapeutic application, a series of novel spirooxindoles was designed and synthesized via regioselective three-component reaction between isatin derivatives, 2-phenylglycine and diverse arylidene-imidazolidine-2,4-diones (Hydantoins). The suggested stereochemistry was ascertained by an X-ray diffraction study and NMR spectroscopy. The resulting tetracyclic heterocycles were screened for their in vitro and in vivo anti-inflammatory and analgesic activity and for their in vitro antimicrobial potency. In vitro antibacterial screening revealed that several derivatives exhibited remarkable growth inhibition against different targeted microorganisms. All tested compounds showed excellent activity against the Micrococccus luteus strain (93.75 µg/mL ≤ MIC ≤ 375 µg/mL) as compared to the reference drug tetracycline (MIC = 500 µg/mL). Compound 4e bearing a p-chlorophenyl group on the pyrrolidine ring exhibited the greatest antifungal potential toward Candida albicans and Candida krusei (MIC values of 23.43 µg/mL and 46.87 µg/mL, respectively) as compared to Amphotericin B (MIC = 31.25 and 62.50 µg/mL, respectively). The target compounds were also tested in vitro against the lipoxygenase-5 (LOX-5) enzyme. Compounds 4i and 4l showed significant inhibitory activity with IC50 = 1.09 mg/mL and IC50 = 1.01 mg/mL, respectively, more potent than the parent drug, diclofenac sodium (IC50 = 1.19 mg/mL). In addition, in vivo evaluation of anti-inflammatory and analgesic activity of these spirooxindoles were assessed through carrageenan-induced paw edema and acetic acid-induced writhing assays, respectively, revealing promising results. In silico molecular docking and predictive ADMET studies for the more active spirocompounds were also carried out.


Assuntos
Anti-Infecciosos , Hidantoínas , Simulação de Acoplamento Molecular , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios/química , Analgésicos/química , Anti-Infecciosos/farmacologia , Antibacterianos/farmacologia , Anticonvulsivantes/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade
11.
J Environ Manage ; 345: 118876, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37678018

RESUMO

Tailings produced by mining engineering and metal smelting industries have become a major challenge to the ecological environment and human health. Environmental compatibility, mechanical stability, and economic feasibility have restricted the treatment and reuse of tailings. A novel solidification/stabilization technology using hydantoin epoxy resin (HER) and red clay for copper tailing treatment was developed, and the leaching behaviors of solidified/stabilized copper tailings were investigated in this paper. The leaching characteristics were analyzed by toxicity characteristic leaching procedure (TCLP) leaching tests. Besides, the influence of red clay content and acid rain on the permeability characteristics and leaching characteristics were investigated based on flexible-wall column tests and microstructure tests. The results showed that the copper tailings solidification/stabilization technology with HER and red clay had excellent performances in toxicity stabilization. The leaching concentration of Cu in TCLP tests and flexible wall column tests remained within the limit specified by the Chinese national standard, and the concentration of Cu decreased significantly with the increase of the red clay content. Moreover, acid rain leaching changed the mineral composition and microstructure of solidified tailings, and the porosity of the samples increased with the dissolution of soluble minerals. Additionally, the hydraulic conductivities decreased slightly with the increase in the pH value of acid rain, and the solidified sample with 5% red clay had the lowest hydraulic conductivity.


Assuntos
Chuva Ácida , Hidantoínas , Metais Pesados , Humanos , Cobre , Argila , Resinas Epóxi , Minerais , Metais Pesados/química
12.
Int J Toxicol ; 42(4): 326-333, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37177794

RESUMO

Historically, formaldehyde was used as a preservative in personal care products to extend product shelf-life; however, given its skin sensitization potential it has been phased out of use and replaced with formaldehyde-releasing preservatives, such as Dimethyloldimethyl hydantoin (DMDMH). A relationship has been established between positive patch test results following exposure to DMDMH and previous sensitization to formaldehyde. Upon direct contact with the skin, formaldehyde can react with skin proteins and cause an acute inflammatory reaction, which may progress to skin sensitization following repeated exposure. This quantitative risk assessment (QRA) aimed to assess the risk of skin sensitization induction following use of shampoo products containing the maximum allowable concentrations of DMDMH in formulation (1% w/v), translating to a free formaldehyde concentration of 0.02%. To determine a margin of safety (MOS) for exposure to DMDMH from use of shampoo products, consumer exposure levels (CEL) were estimated based on typical use scenarios and then benchmarked against an acceptable exposure level (AEL). The AEL was derived using a weight of evidence approach where a range of no expected sensitization induction levels (NESILs) was utilized. The MOS values for a shampoo product containing 1% DMDMH (.02% formaldehyde) was above 1 for the typical use scenario indicating a low likelihood of skin sensitization induction among healthy individuals. Thus, it can be concluded that shampoo products containing DMDMH at or below current allowable concentrations are not expected to increase the risk of skin sensitization induction.


Assuntos
Dermatite Alérgica de Contato , Hidantoínas , Humanos , Dermatite Alérgica de Contato/etiologia , Hidantoínas/toxicidade , Formaldeído/toxicidade , Anticonvulsivantes , Conservantes Farmacêuticos/toxicidade , Medição de Risco/métodos
13.
Chembiochem ; 24(10): e202300143, 2023 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-37042352

RESUMO

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.


Assuntos
Amidoidrolases , Ácido Aspártico , Hidantoínas , Minerais , Origem da Vida , Minerais/síntese química , Minerais/química , Domínio Catalítico , Zinco/química , Amidoidrolases/química , Ciclização , Ácido Aspártico/química , Hidantoínas/química
14.
Int J Mol Sci ; 24(5)2023 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-36902468

RESUMO

Novel hydantion and thiohydantoin-based spiro-compounds were prepared via theDiels-Alder reactions between 5-methylidene-hydantoins or 5-methylidene-2-thiohydantoins and 1,3-dienes (cyclopentadiene, cyclohexadiene, 2,3-dimethylbutadiene, isoprene). It was shown that the cycloaddition reactions proceed regioselectively and stereoselectively with the formation of exo-isomers in the reactions with cyclic dienes andthe less sterically hindered products in the reactions with isoprene. Reactions of methylideneimidazolones with cyclopentadiene proceed viaco-heating the reactants; reactions with cyclohexadiene, 2,3-dimethylbutadiene, and isoprene require catalysis by Lewis acids. It was demonstrated that ZnI2 is an effective catalyst in the Diels-Alder reactions of methylidenethiohydantoins with non-activated dienes. The possibility of alkylation and acylation of the obtained spiro-hydantoinsat the N(1)nitrogen atoms with PhCH2Cl or Boc2O and the alkylation of the spiro-thiohydantoinsat the S atoms with MeI or PhCH2Cl in high yields have been demonstrated. The preparativetransformation of spiro-thiohydantoins into corresponding spiro-hydantoinsin mild conditions by treating with 35% aqueous H2O2 or nitrile oxide has been carried out. The obtained compounds show moderate cytotoxicity in the MTT test on MCF7, A549, HEK293T, and VA13 cell lines. Some of the tested compounds demonstrated some antibacterial effect against Escherichia coli (E. coli) BW25113 DTC-pDualrep2 but were almost inactive against E. coli BW25113 LPTD-pDualrep2.


Assuntos
Hidantoínas , Humanos , Tioidantoínas , Reação de Cicloadição , Escherichia coli , Células HEK293 , Peróxido de Hidrogênio , Ciclopentanos
15.
Eur J Med Chem ; 249: 115147, 2023 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-36739750

RESUMO

Mimics of antimicrobial peptides (AMPs) have been proposed as a promising class of antimicrobial agents. We report the analysis of five tetrasubstituted, cationic, amphipathic heterocycles as potential AMP mimics. The analysis showed that the heterocyclic scaffold had a strong influence on the haemolytic activity of the compounds, and the hydantoin scaffold was identified as a promising template for drug lead development. Subsequently, a total of 20 hydantoin derivatives were studied for their antimicrobial potency and haemolytic activity. We found 19 of these derivatives to have very low haemolytic toxicity and identified three lead structures, 2dA, 6cG, and 6dG with very promising broad-spectrum antimicrobial activity. Lead structure 6dG displayed minimum inhibitory concentration (MIC) values as low as 1 µg/mL against Gram-positive bacteria and 4-16 µg/mL against Gram-negative bacteria. Initial mode of action (MoA) studies performed on the amine derivative 6cG, utilizing a luciferase-based biosensor assay, suggested a strong membrane disrupting effect on the outer and inner membrane of Escherichia coli. Our findings show that the physical properties and structural arrangement induced by the heterocyclic scaffolds are important factors in the design of AMP mimics.


Assuntos
Anti-Infecciosos , Hidantoínas , Hidantoínas/farmacologia , Anti-Infecciosos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Bactérias Gram-Negativas , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/química
16.
Molecules ; 28(2)2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36677661

RESUMO

Indoles and hydantoins are important heterocycles scaffolds which present in numerous bioactive compounds which possess various biological activities. Moreover, they are essential building blocks in organic synthesis, particularly for the preparation of important hybrid molecules. The series of hybrid compounds containing indoles and imidazolidin-2-one moiety with direct C-C bond were synthesized using an amidoalkylation one-pot reaction. All compounds were investigated as a growth regulator for germination, growth and development of wheat seeds (Triticum aestivum L). Their effect on drought resistance at very low concentrations (4 × 10-5 M) was evaluated. The study highlighted identified the leading compounds, 3a and 3e, with higher growth-regulating activity than the indole-auxin analogues.


Assuntos
Hidantoínas , Indóis , Indóis/farmacologia , Indóis/química , Anticonvulsivantes , Hidantoínas/farmacologia , Ácidos Indolacéticos
17.
Biomater Sci ; 11(5): 1785-1796, 2023 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-36648752

RESUMO

An elaborate design of multimodal antibacterial agents has been revealed to be a promising strategy to address bacterial resistance, originating from the abuse of antibiotics. In this work, we have developed a positively charged and porous material, FePPOPHydantoin, as a disinfectant via introducing 1,3-dibromo-5,5-dimethylhydantoin (Hydantoin) and porphyrin iron units into a polymer framework. The extended π conjugated networks of FePPOPHydantoin endowed the material with strong near-infrared (NIR) absorption, high density of surface catalytic active centers, superior stability, and reproducibility. FePPOPHydantoin exhibits high peroxidase mimetic and photo-Fenton activity, which can catalyze the biologically allowable maximum concentrations of hydrogen peroxide (100 µM) to produce a vast amount of hydroxyl radicals. Simultaneously, the effective electrostatic interaction between the positively charged FePPOPHydantoin and the negatively charged bacteria facilitates the binding of FePPOPHydantoin on the bacterial membrane, restricting bacteria within the destruction range of hydroxyl radicals and thus making the bacteria more vulnerable. Finally, further close contact between bacteria and Hydantoin units in FePPOPHydantoin gave the material an antibacterial efficiency of over 99.999%. Compared with chemical therapy, photo-Fenton therapy, or peroxidase catalytic therapy alone, FePPOPHydantoin had a noteworthy multi-amplified antibacterial efficiency. Furthermore, FePPOPHydantoin exhibited good biocompatibility and negligible cytotoxicity. The in vivo antibacterial therapy on the Staphylococcus aureus (S. aureus) infected mouse wound model clearly proved the effectiveness of FePPOPHydantoin for fighting bacterial infections. This work highlights opportunities for the design of nanozymes with enhanced bacteriostatic activity, providing a new avenue for the construction of novel antibiotics.


Assuntos
Hidantoínas , Metaloporfirinas , Camundongos , Animais , Escherichia coli , Hidantoínas/farmacologia , Staphylococcus aureus , Reprodutibilidade dos Testes , Peroxidase/metabolismo , Peroxidases/farmacologia , Antibacterianos/farmacologia , Peróxido de Hidrogênio/farmacologia
18.
Biosci Biotechnol Biochem ; 87(4): 411-419, 2023 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-36694933

RESUMO

In our previous study, ertABC genes encoding ergothionase, thiourocanate hydratase, and 3-(5-oxo-2-thioxoimidazolidin-4-yl) propionic acid desulfhydrase were identified, all of which may be involved in ergothioneine utilization of Burkholderia sp. HME13. In this study, we identify the ertD gene encoding metal-dependent hydantoin-5-propionic acid amidohydrolase in this strain. Mn2+-containing ErtD showed maximum activity at 45 °C and pH 8.5 and was stable at temperatures up to 45 °C. The Km and Vmax values of Mn2+-containing ErtD for hydantoin-5-propionic acid were 2.8 m m and 16 U/mg, respectively. Real-time polymerase chain reaction (PCR) revealed that ertD expression levels in Burkholderia sp. HME13 cells cultivated in ergothioneine medium were 3.3-fold higher than those in cells cultivated in Luria-Bertani (LB) medium. ErtD activity in the crude extract from Burkholderia sp. HME13 cells cultured in ergothioneine medium was 0.018 U/mg, whereas that in LB medium was not detected. Accordingly, we suggest that ErtD is involved in ergothioneine utilization in this strain.


Assuntos
Burkholderia , Ergotioneína , Hidantoínas , Amidoidrolases/metabolismo , Burkholderia/genética , Burkholderia/metabolismo , Hidantoínas/metabolismo
19.
Int J Mol Sci ; 24(2)2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36674803

RESUMO

Nitrile imine cycloaddition to hydantoins containing an exocyclic C=C double bond has been previously described in a very limited number of examples. In this work, regioselective synthesis of spiro-pyrazoline-imidazolidine-2,4-diones based on a 1,3-dipolar cycloaddition reaction of nitrile imines to 5-methylidene-3-phenyl-hydantoin have been proposed. It was found that, regardless of the nature of the aryl substituents at the terminal C and N atoms of the C-N-N fragment of nitrile imine (electron donor or electron acceptor), cycloaddition to the 5-methylidenhydantoin exocyclic C=C bond proceeds regioselectively, and the terminal nitrogen atom of the nitrile imine connects to the more sterically hindered carbon atom of the double bond, which leads to the formation of a 5-disubstituted pyrazoline ring. The observed cycloaddition regioselectivity was rationalized using DFT calculations of frontier molecular orbital interactions, global CDFT reactivity indices, and minimum energy paths.


Assuntos
Hidantoínas , Reação de Cicloadição , Teoria da Densidade Funcional , Iminas/química , Nitrilas/química , Anticonvulsivantes
20.
J Org Chem ; 88(15): 10381-10402, 2023 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-36226862

RESUMO

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.


Assuntos
Hidantoínas , Peptidomiméticos , Hidantoínas/química , Conformação Molecular , Modelos Moleculares , Ciclização , Dicroísmo Circular , Espectroscopia de Infravermelho com Transformada de Fourier
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