Hydantoin Derivatives Research Articles

In vitro α-Glucosidase Inhibition, Cytotoxicity, SAR, Swiss ADME Prediction and Molecular Docking Study of New N-Substituted Hydantoin Derivatives.

Diabetes is a chronic metabolic disorder affecting about 463 million people globally. α-Glucosidase (EC.3.2.1.20) inhibitors are among the FDA-approved oral anti-diabetic medications used to treat type 2 diabetes. In search of new potential α-glucosidase inhibitors, fifteen of our previously synthesized hydantoin derivatives 8 a-o were evaluated for their antidiabetic activity. All compounds 8 a-o showed weak α-glucosidase inhibition at 10, 50 and 100 μM. However, at 200 μM, compound 8 o was the most potent among the series followed by compounds 8 a, 8 d, 8 l and 8 n exhibiting moderate inhibition. The established SAR depended upon the exchange of methyl with methoxy and dioxole derivatives at positions 3 and 4 of the phenyl ring. Cytotoxicity studies revealed that most of the compounds have no cytotoxic effect. Furthermore, Swiss ADME predictions of compounds 8 a, 8 d, 8 i, 8 l and 8 o showed high gastrointestinal intestinal absorption required for intestinal absorption of any drug. Most compounds did not obey drug-likeness character since they violated Ghose and Veber rules with MW>350 and rotors>11. Molecular docking was carried out to investigate the binding interaction of compounds with the active site of α-glucosidase. The results correlated well with those of the experimental, thereby contributing towards the development of new α-glucosidase inhibitors.

Benzalhydantoin Derivative-Based Inhibitors of Eight Receptor Tyrosine Kinases: Synthesis, in-vitro, and in-silico Study

Some hydantoin derivatives have been explored for their potential as anticancer agents by inhibiting receptor tyrosine kinases (RTKs). Benzalhydantoin derivatives were obtained from a two-step reaction: condensation and alkylation reaction. The benzalhydantoin activities were obtained from the enzymatic assay, while the molecular interaction was simulated with molecular docking. Five known compounds (5-9) and two new benzalhydantoin derivatives 10-11 have been synthesized from the appropriate precursors with 4-71% yields. The structures of the compounds were determined mainly by NMR and mass spectral data. From the chemical shift of the H-7’, the configuration of the products 5, 7, 9-11 were determined as Z-isomer, while 6 and 8 were defined as E-isomer. A bioassay of the seven derivatives at 10 µM against eight receptor tyrosine kinases (EGFR, HER2, HER4, IGF1R, InsR, VEGFR-2, and PDGFR-α and -β) showed that 8 ((Z)-5-8:(Z)-5-(4'-hydroxy-3'methoxybenzylidene)imidazolidine-2,4-dione and 10: (Z)-5-(4'-methoxybenzylidene) imidazolidine-2,4-dione were moderately active against VEGFR-2, with inhibition of 46 and 56%, respectively. In addition, 8 was also active against PDGFR-α and -β, with a 57% inhibition. Further evaluation of 8 and 10 using AutoDock4 showed their binding energy interactions with VEGFR2 (PDB ID: 4AG8) around -6.96 and -7.32 kcal/mol, respectively. Thus, both compounds are potential candidates to be optimized further as inhibitors of angiogenesis blood vessel development.

Thermal-Mediated Synthesis of Hydantoin Derivatives from Amino Acids via Carbodiimide Reagents

We introduce an innovative methodology for synthesizing hydantoins from amino acids using readily available carbodiimides, emphasizing the crucial role of temperature in the reaction process. This approach presents significant advantages over conventional methods involving isocyanates, facilitating easier handling and minimizing associated risks. Our strategy not only allows for the efficient production of a diverse array of hydantoin derivatives but also adheres to environmentally sustainable practices. The optimized reaction conditions enhance efficiency, marking a significant advancement in the field of organic synthesis. This method presents significant advantages for industrial applications, as it is a heat-mediated process that does not require the use of any bases or catalysts. By eliminating the need for additional reagents, this approach simplifies the reaction conditions, reduces potential side reactions, and minimizes the overall environmental impact. Additionally, the absence of catalysts streamlines the purification process, making it more cost-effective and efficient for large-scale production.

Recent Development in Hydantoins, Thiohydantoins, and Selenohydantoins as Anticancer Agents: Structure-activity Relationship and Design Strategies.

Hydantoin, a five-membered heterocyclic scaffold, is regarded as a crucial scaffold in medicinal chemistry. Hydantoins have been useful in synthesizing medicines like nilutamide, enzalutamide, and apalutamide. Thiohydantoin and selenohydantoin have been discovered as two separate types of hydantoin. There are two hydrogen bond donors, two hydrogen bond acceptors, and four substitution sites. These characteristics have led to the design, synthesis, and expansion of hydantoin derivatives' biological and pharmacological effects against numerous types of malignancies. This study reviews the recent contributions of hydantoin and its isosteric variants to medicinal chemistry. To emphasize their significance, certain significant compounds based on hydantoins and their structure activity relationships (SAR) are briefly discussed. We thoroughly analyzed each scaffolds' structural characteristics and SAR, and these scaffolds may one day show potential anticancer activities.

Effect of Atomic Size and Stereochemistry of Halogenated Hydantoin Derivatives on Main Protease Inhibition Activities of SARS-CoV-2: Rationalization Through Computational Studies

Effect of Atomic Size and Stereochemistry of Halogenated Hydantoin Derivatives on Main Protease Inhibition Activities of SARS-CoV-2: Rationalization Through Computational Studies

Phenytoin-induced cerebellar symptoms – A case report

Phenytoin, a hydantoin derivative, is an effective anticonvulsant drug widely used to treat seizure disorder. The wide pharmacokinetic variability and low toxicity threshold of phenytoin often contribute to its toxicity. We now report the case of a 43-year-old woman who was hospitalized with ataxia, nystagmus, external ophthalmoplegia, drowsiness, gingival hypertrophy, vomiting, and generalized weakness for 10 days while she was on treatment with T. phenytoin 200 mg/day for the past 6 months for seizure disorder. Two days before the onset of these symptoms, the dose of T. phenytoin was increased from 200 mg/day to 300 mg/day. Based on her signs, symptoms, and laboratory tests, she was diagnosed with phenytoin-induced poisoning. After stopping the medication, the symptoms improved. She started using oral levetiracetam instead. Based on the Naranjo and the World Health Organization, a causal analysis of the relationship between the patient’s symptoms and phenytoin use was done. The severity of this adverse drug reaction is moderate at level 4 on the Hartwig severity rating scale. These data highlight the adverse effects of phenytoin and the importance of clinical monitoring for a drug with a narrow therapeutic index.

Evaluating Anticonvulsant and Neuroprotective potentials of New Hydantoin Derivatives in PTZ and MES Models

Evaluating Anticonvulsant and Neuroprotective potentials of New Hydantoin Derivatives in PTZ and MES Models

Synthesis, Absolute Configuration, Biological Profile and Antiproliferative Activity of New 3,5-Disubstituted Hydantoins.

Hydantoins, a class of five-membered heterocyclic compounds, exhibit diverse biological activities. The aim of this study was to synthesize and characterize a series of novel 3,5-disubstituted hydantoins and to investigate their antiproliferative activity against human cancer cell lines. The new hydantoin derivatives 5a-i were prepared as racemic mixtures of syn- and anti-isomers via a base-assisted intramolecular amidolysis of C-3 functionalized β-lactams. The enantiomers of syn-5a and anti-hydantoins 5b were separated by preparative high-performance liquid chromatography (HPLC) using n-hexane/2-propanol (90/10, v/v) as the mobile phase. The absolute configuration of the four allyl hydantoin enantiomers 5a was assigned based on a comparison of the experimental electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectra with those calculated using density functional theory (DFT). The antiproliferative activity evaluated in vitro against three different human cancer cell lines: HepG2 (liver hepatocellular carcinoma), A2780 (ovarian carcinoma), and MCF7 (breast adenocarcinoma), and on the non-tumor cell line HFF1 (normal human foreskin fibroblasts) using the MTT cell proliferation assay. In silico drug-like properties and ADMET profiles were estimated using the ADMET Predictor ver. 9.5 and the online server admetSAR. Eighteen new 3,5-disubstituted hydantoins were synthesized and characterized. The compound anti-5c showed potent cytotoxic activity against the human tumor cell line MCF7 (IC50 = 4.5 µmol/L) and the non-tumor cell line HFF1 (IC50 = 12.0 µmol/L). In silico analyzes revealed that the compounds exhibited moderate water solubility and membrane permeability and are likely substrates for CYP3A4 and P-glycoprotein and have a high probability of antiarthritic activity.

The Multifaceted Biological Activities of Hydantoin Derivatives: From Antimicrobial to Anticancer Agents

Hydantoin derivatives, a versatile class of heterocyclic compounds, have garnered significant attention in recent years due to their diverse biological activities. These derivatives exhibit a wide range of pharmacological properties, making them valuable candidates in the development of therapeutic agents. This review highlights the multifaceted biological activities of Hydantoin derivatives, with a focus on their antimicrobial and anticancer properties. The antimicrobial efficacy of these compounds encompasses activity against various bacterial, fungal, and viral pathogens, presenting them as potential alternatives to conventional antibiotics. Additionally, Hydantoin derivatives have shown promising anticancer activities by inducing apoptosis, inhibiting cell proliferation, and interfering with various cellular signaling pathways. The structural modifications of these derivatives play a crucial role in enhancing their biological activities, providing insights into structure-activity relationships. Moreover, their potential to overcome drug resistance and reduce side effects associated with traditional therapies underscores their therapeutic significance. This review aims to provide a comprehensive overview of the recent advancements in the biological applications of Hydantoin derivatives, emphasizing their role as promising candidates for future drug development in antimicrobial and anticancer therapy. Further research and clinical studies are warranted to fully explore their therapeutic potential and translate these findings into clinical practice.

Chemical Behavior and Bioactive Properties of Spinorphin Conjugated to 5,5'-Dimethyl- and 5,5'-Diphenylhydantoin Analogs.

The discovery of new peptides and their derivatives is an outcome of ongoing efforts to identify a peptide with significant biological activity for effective usage as a possible therapeutic agent. Spinorphin peptides have been documented to exhibit numerous applications and features. In this study, biologically active peptide derivatives based on novel peptide analogues of spinorphin conjugated with 5,5'-dimethyl (Dm) and 5,5'-diphenyl (Ph) hydantoin derivatives have been successfully synthesized and characterized. Scanning electron microscopy (SEM) and spectral methods such as UV-Vis, FT-IR (Fourier Transform Infrared Spectroscopy), CD (Circular Dichroism), and fluorimetry were used to characterize the microstructure of the resulting compounds. The results revealed changes in peptide morphology as a result of the restructuring of the aminoacidic sequences and aromatic bonds, which is related to the formation of intermolecular hydrogen bonds between tyrosyl groups and the hydantoin moiety. Electrochemical and fluorescence approaches were used to determine some physicochemical parameters related to the biological behavior of the compounds. The biological properties of the spinorphin derivatives were evaluated in vivo for anticonvulsant activity against the psychomotor seizures at different doses of the studied peptides. Both spinorphin analog peptides with Ph and Dm groups showed activity against all three phases of the seizure in the intravenous Pentylenetetrazole Seizure (ivPTZ) test. This suggests that hydantoin residues do not play a crucial role in the structure of spinorphin compounds and in determining the potency to raise the seizure threshold. On the other hand, analogs with a phenytoin residue are active against the drug-resistant epilepsy test (6-Hz test). In addition, bioactivity analyses revealed that the new peptide analogues have the potential to be used as antimicrobial and antioxidant compounds. These findings suggest promising avenues for further research that may lead to the development of alternative medicines or applications in various fields beyond epilepsy treatment.

Discovery of novel benzimidazole derivatives as potent HDACs inhibitors against leukemia with (Thio)Hydantoin as zinc-binding moiety: Design, synthesis, enzyme inhibition, and cellular mechanistic study

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.

Synthesis and biological evaluation of hydantoin derivatives as potent antiplasmodial agents

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.

Hydantoin-D,L-valine: Synthesis, characterization, and non-covalent interaction analysis from crystallographic studies, DFTB calculations, and Hirshfeld surface analysis

The title compound, hydantoin-D,L-daline or (RS)-5-isopropyl-imidazolidine-2,4‑dione, a new amino acid hydantoin derivative with formula C6H10N2O2 has been synthesized and structurally characterized by FT-IR, NMR, and X-ray diffraction techniques. Spectroscopy results are consistent with the skeleton structure. The powder X-ray diffraction data confirms the phase purity of the crystalline sample. Single-crystal X-ray diffraction analysis indicated that the title compound crystallizes in the monoclinic space group P21/c (N°14), Z = 4, and unit cell parameters a = 5.493(3) Å, b = 23.53(2) Å, c = 6.254(3) Å, β= 115.09(4)°, V = 732.1(9) Å3. The molecular structure and crystal packing are stabilized by intermolecular N–H···O, C–H···O, and C–H···π hydrogen bonds forming an infinite two-dimensional network with chains described by the graph-set notation C(5), and centrosymmetric rings with graphs R22(8) and R44(16). The non-covalent interactions were analyzed employing DFTB calculations, which reproduce the main features of the stereochemistry and geometries exhibited by X-ray diffraction. Additionally, these intermolecular interactions were analyzed using Hirshfeld surfaces analysis and 2D fingerprint plots.

Synthesis of Some New Hydantoin Derivatives with Possible Anticonvulsant And Analgesic Activities

Synthesis of Some New Hydantoin Derivatives with Possible Anticonvulsant And Analgesic Activities

Hydantoin derivative dimers as broad-spectrum antimicrobial agents against ESKAPE pathogens with enhanced killing rate and stability.

A new series of hydantoin derivative dimers as potential broad-spectrum antibiotic agents is designed and synthesized to combat ESKAPE pathogens. As membrane-active antimicrobial agents, in addition to cationic charged and hydrophobic groups that mimic AMPs (antimicrobial peptides), hydantoin backbones and aromatic linkers increased the rigidity and lipophilicity of the designed compounds, thus improving the stability and bactericidal killing rate. After whole cell phenotypic screening against eight bacterial strains, including MRSA (methicillin-resistant S. aureus), compound 18 was chosen as the lead compound with overall excellent broad-spectrum antibacterial activity (GM = 7.32 μg mL-1) and good selectivity. Kill-kinetic studies of compound 18 showed that the bacterial growth of both Gram-positive and Gram-negative was completely inhibited within one hour, which demonstrated excellent sterilization efficiency of 18. Furthermore, drug resistance and mechanism studies showed that compound 18 exhibited a steady antibacterial performance during 25 passages and could disrupt bacterial cell membrane integrity and cause cell death. Along with the facile synthesis procedures in solution, this series of hydantoin derivative dimer compounds could be an appealing next generation of antibiotic agents to combat emergent drug resistance.

Hydantoin derivatives: A review on their anticancer activities

Hydantoin derivatives: A review on their anticancer activities

Synthesis, antimicrobial activity and molecular docking studies of novel hydantoin derivatives as potential phospholipase A2 inhibitors

This work presents the synthesis, characterization and evaluation of a series of new multifunctional N-substituted hydantoin derivatives for their antibacterial and antifungal activity. Elemental analysis, 1H NMR, 13C NMR, and mass spectroscopy were used to confirm the newly synthesized compounds' structure. The antibacterial and antifungal properties of each synthesized molecule were examined. The examined compounds showed significant to moderate antimicrobial activity against the tested Gram-positive, Gram-negative, and fungal strains with MIC values ranging from 10.3 to 84.2 µM. Compounds 22 (MIC: 11.7–13.5 µM) and 25 (MIC: 10.2–11.9 µM) demonstrated an impressive MIC value against the tested bacterial and fungal strains when compared to the reference medications fluconazole (MIC: 11.7–14.5 µM) and streptomycin (MIC: 14.5 µM), which are broad-spectrum antibiotics and antifungal agents, respectively. Additionally, all of the compounds were tested for their ability to inhibit the phospholipase A2 (PLA2) enzyme, with the IC50 values ranging from 8.53 to 65.14 µM. When compared to the reference drug ursolic acid (IC50: 12.58 µM), compounds 22 (IC50: 10.27 µM) and 25 (IC50: 8.53 µM) were shown to be the most potent PLA2 inhibiting compounds in this series. The findings of the Molecule description with Drug-Likeness Prediction demonstrated that all the compounds are in a linear correlation with Lipinski's rule of five, demonstrating good drug-likeness qualities. The inhibitory effects of the most potent compounds (18, 19, 22 and 25) against the target PLA2 protein (PDB ID: 2H4C) were explained by molecular docking studies. The molecular docking results were in good accord with the experimental findings, and as these compounds had superior binding affinities within the active pocket, they may be classified as potent inhibitors of specific targets.

Novel hydantoin derivatives: Synthesis and biological activity evaluation

Novel compounds derived from hydantoin were synthesized using a chloroacetyl chloride linker in conjunction with terminal compounds of sulphonamides and amines. The compounds were subjected to various analytical techniques, including LC-MS/MS, 1H NMR, 13C NMR, FT-IR, and determination of melting point. Subsequently, the synthesized compounds were evaluated for their potential anti-cancer properties (against) breast cancer (MCF-7) and lung cancer (A549) cell lines by the MTT assay. Additionally, the compounds' anticonvulsant activity was assessed using pentylenetetrazol (PTZ)-induced seizure in mice. Furthermore, the inhibitory activity of selected compounds against the PI3Kα enzyme at a concentration of 100 µM was investigated. The biological evaluation of the compounds did not show the expected anticonvulsant effect when tested at various doses (5, 10, and 20 mg/kg b.w using the intraperitoneal injection), with all mice showing a seizure score of 5. MTT assay showed moderate anti-cancer activity against, the (A549) cell line, with compound 37 exhibiting the highest inhibition of cell viability at 55.1%. In the case of the breast cancer cell line, compounds 37, 40, 42, and 45 demonstrated inhibition percentages ranging from 64% to 74%. Moreover, the compounds displayed a relatively limited inhibitory effect on PI3Kα activity during the in-vitro evaluation compared to staurosporine. These findings suggest that further optimization and modification of the synthesized compounds may be necessary to enhance their anticonvulsant and anti-cancer properties, particularly regarding PI3Kα inhibition.

Theoretical calculation of the adiabatic electron affinity and vertical electron affinity of some hydantoin drugs

Several DFT approaches with 6–311 + G(2df,2p) basis set at the B3LYP/6–31 + G(d,p) geometries were examined to calculate accurate adiabatic electron affinity (AEA) for some hydantoin derivatives. The accuracy of these approaches was statistically examined with respect to the standard reference AEA, which obtained by using G4, G3B3 and CBS-QB3 methods. The results reveal that the least RMSE values were obtained for B3PW91, TPSSTPSS and B3LYP approaches, respectively. The B3PW91 approach in conjunction with the 6–311 + G(2df,2p) basis set at the B3LYP/6–31 + G(d,p) geometries were used to calculate the AEA for some hydantoin drugs, including Phenytoin, Nitrofurantoin, Allantoin, Iprodine, Ethotoin and Mephenytoin, as well as some of phenytoin and nitrofurantoin derivatives. Moreover, the vertical electron affinity (VEA) of all investigated compounds were calculated using the B3LYP/6–31 + G(d,p) level. The substitution effects on the AEA values were studied and discussed. The results reveal that the electron donating groups decrease the AEA and VEA value, whereas, the reverse is true in the case of the electron withdrawing groups. Furthermore, NBO analysis was used to calculate the natural spin density and atomic charges of the neutral and anion species. The results obtained show, in general, that the maximum spin density is located on the carbonyl carbon atom of the hydantoin ring. The changes in the geometrical structures (bond lengths and bond angles) of anions compared to the neutral molecules were also studied and discussed. Correlations between the AEA and VEA with the energy gap with the correlation coefficients (R2) close to unity were shown. Furthermore, the AEA and VEA for some hydantoin derivatives and drugs were also calculated in aqueous solution, and their results are compared with the gas phase results.

Substitution effect on the adiabatic ionization potential, vertical ionization potential, electrophilicity, and nucleophilicity of some hydantoin drug derivatives: Computational study

AbstractIn the current paper, the adiabatic ionization potentials (AIP) for 29 hydantoin derivatives and hydantoin‐based drugs such as allantoin, phenytoin, mephenytoin, nilutamide, iprodione, nitrofurantoin, and ethotoin were calculated using the double hybrid ωB97XD density functional theory (DFT) in coupling with 6‐311+G(2df,2p) basis set at the B3LYP/6‐31+G(d,p) optimized geometry. The neutral and cationic radicals of the examined species were firstly optimized using the B3LYP/6‐31+G(d,p) level. Final energies were improved by single point calculation using 16 different DFT methods such as B3LYP, ωB97, B97D, TPSSTPSS, M06‐2X, …, and so forth, with 6‐311+G(2df,2p) basis. Statistical tools such as root mean square error (RMSE) was used to examine the accuracy of the DFT method with respect to the standard reference AIP values. These standard references were calculated, for 12 hydantoin derivatives with less than nine non‐hydrogen atoms, by taking the average values of the AIP computed using the G4, G3B3, and CBS‐QBS methods. The vertical ionization potentials (VIPs), the vertical electron affinity (VEA), and global quantum parameters such as electrophilicity and nucleophilicity of the 29 molecules were also calculated. Substitution effect on the AIP, VIP, VEA, fundamental gap, electrophilicity, and nucleophilicity of the species under probe was studied and discussed. The results reveal that substitution of electron withdrawing group (EWG) raises the AIP and VIP, electrophilicity, and the fundamental gap, while substitution of electron donating group (EDG) raises the VEA and the nucleophilicity. Furthermore, the condensed Fukui functions were used to identify the active centers for nucleophilic, electrophilic, and free radical attacks.