Synthesis and characterization of new 5,5′-dimethyl- and 5,5′-diphenylhydantoin-conjugated hemorphin derivatives designed as potential anticonvulsant agents

Todorov, Petаr; Peneva, Petia; Georgieva, Stela; Tchekalarova, Jana; Rangelov, Miroslav; Todorova, Nadezhda

doi:10.1039/d1nj05235g

Cited by 8 publications

(10 citation statements)

References 71 publications

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“…The test was conducted as described in our previous study [19]. In brief, an electric stimulus of 50 mA, 60 Hz, 0.2 s was applied individually to each tested mouse via corneal electrodes (Constant Current Shock Generator).…”

Section: Mes Testmentioning

confidence: 99%

“…Recently, we reported that newly synthesized peptide phenytoin derivatives exhibited anticonvulsant activity in several rodent tests [19]. In addition, the structure-biological activity relationship gave us the grounds to further characterize the novel 5,5′-diphenylhydantoins by incorporating some substituents into the N3 position of the hydantoin ring [20].…”

Section: Introductionmentioning

confidence: 99%

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Additive Anticonvulsant Profile and Molecular Docking Analysis of 5,5′-Diphenylhydantoin Schiff Bases and Phenytoin

Tchekalarova,

Todorov,

Rangelov

et al. 2023

Biomedicines

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Four 5,5′-diphenylhydantoin Schiff bases possessing different aromatic species (SB1–SB4) were recently synthesized and characterized using spectroscopic and electrochemical tools. The present study aimed to ascertain the anticonvulsant activity of the novel phenytoin derivatives SB1-Ph, SB2-Ph, SB3-Ph, and SB4-Ph, containing different electron-donor and electron-acceptor groups, and their possible mechanism of action. The SB2-Ph exhibited the highest potency to suppress the seizure spread with ED50 = 8.29 mg/kg, comparable to phenytoin (ED50 = 5.96 mg/kg). While SB2-Ph did not produce neurotoxicity and sedation, it decreased locomotion and stereotypy compared to control. When administered in combination, the four Schiff bases decreased the phenytoin ED50 by more than 2× and raised the protective index by more than 7× (phenytoin+SB2-Ph). The strongest correlation between in-vivo and docking study results was found for ligands’ interaction energies with kappa and delta receptors. These data, combined with the worst interaction energies of our ligands with the mu receptor, suggest that the primary mechanism of their action involves the kappa and delta receptors, where the selectivity to the kappa receptor leads to higher biological effects. Our findings suggest that the four Schiff bases might be promising candidates with potential applications as a safe and effective adjuvant in epilepsy.

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Section: Mes Testmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Additive Anticonvulsant Profile and Molecular Docking Analysis of 5,5′-Diphenylhydantoin Schiff Bases and Phenytoin

Tchekalarova,

Todorov,

Rangelov

et al. 2023

Biomedicines

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“…When a spinorphin molecule is mixed with structures that have been shown to have a biological effect, they work together to improve biological functions [ 9 ]. Phenytoin is a hydantoin-based anticonvulsant drug commonly used to inhibit the spread of seizures in the brain by reducing the excessive activation of neurons [ 18 ]. Research has shown that the compound affects the movement of substances across cell membranes, reducing the amount of sodium ions within the cell and causing hyperpolarization of the cell membrane.…”

Section: Introductionmentioning

confidence: 99%

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

Georgieva,

Todorov,

Tchekalarova

et al. 2024

Pharmaceuticals

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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.

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“…The discovery of biologically active compounds embedded in spirooxinole and hydantoin scaffolds prompted us to investigate further modifications within this class of compounds. Similarly, hydantoin derivatives (imidazolidine-2,4-diones) [28,29] emerged as privileged scaffolds in medicinal chemistry due to their various biological and therapeutic applications such as anticancer [30][31][32], anti-inflammatory [33][34][35], antidiabetic [36], anticonvulsant [37,38] and antimicrobial agents [39]. With such broad bioactivities, many hydantoin derivatives featured in several clinically used drugs such as phenytoin (anti-epileptic agent) [40], nilutamide (nonsteroidal androgen antagonists) [41] and nitrofurantoin (antibiotic for the treatment of infections caused by multi-drug resistant pathogens) (Figure 1) [42].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Tetracyclic Spirooxindolepyrrolidine-Engrafted Hydantoin Scaffolds: Crystallographic Analysis, Molecular Docking Studies and Evaluation of Their Antimicrobial, Anti-Inflammatory and Analgesic Activities

Toumi,

Abdella,

Boudriga

et al. 2023

Molecules

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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.

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Synthesis and characterization of new 5,5′-dimethyl- and 5,5′-diphenylhydantoin-conjugated hemorphin derivatives designed as potential anticonvulsant agents

Abstract: Herein, the synthesis and characterization of some novel N-modified hybrid analogues of hemorphins containing a C-5 substituted hydantoin residue as potential anticonvulsants and for the blockade of sodium channels are presented.

Cited by 8 publications

References 71 publications

Additive Anticonvulsant Profile and Molecular Docking Analysis of 5,5′-Diphenylhydantoin Schiff Bases and Phenytoin

Additive Anticonvulsant Profile and Molecular Docking Analysis of 5,5′-Diphenylhydantoin Schiff Bases and Phenytoin

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

Synthesis of Tetracyclic Spirooxindolepyrrolidine-Engrafted Hydantoin Scaffolds: Crystallographic Analysis, Molecular Docking Studies and Evaluation of Their Antimicrobial, Anti-Inflammatory and Analgesic Activities

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