Search Results (20)

Spiroleiferthione A (1), with a 2-thiohydantoin a heterocyclic spiro skeleton, and oleiferthione A (2), an imidazole-2-thione derivative, were isolated from the aqueous extract of Moringa oleifera Lam. seeds. The unprecedented structures of 1 and 2 were elucidated by extensive spectroscopic data, X-ray diffraction, and gauge-independent atomic orbital (GIAO) NMR calculation, as well as electronic circular dichroism (ECD) calculation. The structures of 1 and 2 were determined to be (5R,7R,8S)-8-hydroxy-3-(4′-hydroxybenzyl)-7-methyl-2-thioxo-6-oxa-1, 3-diazaspiro [4.4] nonan-4-one, and 1-(4′-hydroxybenzyl)-4,5-dimethyl-1,3-dihydro-2H-imidazole-2-thione, respectively. Biosynthetic pathways for 1 and 2 have been proposed. Compounds 1 and 2 are considered to have originated from isothiocyanate and then undergone a series of oxidation and cyclization reactions to form 1 and 2. Compounds 1 and 2 demonstrated weak inhibition rates of NO production, 42.81 ± 1.56% and 33.53 ± 2.34%, respectively, at a concentration of 50 μM. Additionally, Spiroleiferthione A demonstrated moderate inhibitory activity against high glucose-induced human renal mesangial cell proliferation in a dosage-dependent manner. A wider range of biological activities, and the diabetic nephropathy protective activity of Compound 1 in vivo and its mechanism of action, need further investigation after the sufficient enrichment of Compound 1 or total synthesis. Full article

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. Full article

Novel variously substituted thiohydantoin-based dispiro-indolinones were prepared using a regio- and diastereoselective synthetic route from 5-arylidene-2-thiohydantoins, isatines, and sarcosine. The obtained molecules were subsequently evaluated in vitro against the cancer cell lines LNCaP, PC3, HCT^wt, and HCT^(−/−). Several compounds demonstrated a relatively high cytotoxic activity vs. LNCaP cells (IC₅₀ = 1.2–3.5 µM) and a reasonable selectivity index (SI = 3–10). Confocal microscopy revealed that the conjugate of propargyl-substituted dispiro-indolinone with the fluorescent dye Sulfo-Cy5-azide was mainly localized in the cytoplasm of HEK293 cells. P388-inoculated mice and HCT116-xenograft BALB/c nude mice were used to evaluate the anticancer activity of compound 29 in vivo. Particularly, the TGRI value for the P388 model was 93% at the final control timepoint. No mortality was registered among the population up to day 31 of the study. In the HCT116 xenograft model, the compound (170 mg/kg, i.p., o.d., 10 days) provided a T/C ratio close to 60% on day 8 after the treatment was completed. The therapeutic index—estimated as LD₅₀/ED₅₀—for compound 29 in mice was ≥2.5. Molecular docking studies were carried out to predict the possible binding modes of the examined molecules towards MDM2 as the feasible biological target. However, such a mechanism was not confirmed by Western blot data and, apparently, the synthesized compounds have a different mechanism of cytotoxic action. Full article

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. Full article

As the ninth leading cause of death globally, diabetes mellitus (DM) is considered to be the worst chronic metabolic disease requiring an enormous need for healthcare with over 578 million expected cases by 2023. Several recent findings have demonstrated that mediating the activity of carbohydrate-hydrolyzing enzymes, including α-amylase and α-glucosidase, could be a potential strategy for managing the development of DM. In the presented study, a novel set of 1,3,5-trisubstituted-2-thioxoimidazolidin-4-ones was designed, synthesized, and characterized. The antidiabetic activity of the synthesized compounds was explored by assessing their inhibitory activity toward α-amylase and α-glucosidase enzymes. The results demonstrated that this class of compounds exhibits considerable inhibitory activity toward both α-amylase and α-glucosidase enzymes. Among the synthesized compounds, compound 5a demonstrated the most inhibitory activity with IC₅₀ of 5.08 and µg/mL and 0.21 µg/mL toward α-glucosidase and α-amylase activities, respectively, as compared to the drug Acarbose (IC₅₀ = 5.76 µg/mL and 0.39 µg/mL, respectively). To gain insights into the antidiabetic potential of compound 5a, we assessed the cytotoxic and antioxidant activities. Our findings indicated that compound 5a displays considerable cytotoxicity toward WI-38 cells with an IC₅₀ of 88.54 µg/mL, as compared to the drug Celecoxib (IC₅₀ = 93.05 µg/mL). Further, compound 5a exhibited a high scavenging activity toward 2,2-Diphenyl1-picrylhydrazyl (DPPH) free radicals (IC₅₀ = 51.75 µg/mL) and showed a low potential to produce ROS as indicated by the monitoring of the generated H₂O₂ (132.4 pg/mL), as compared to Trolox (IC₅₀ = 58.09 µg/mL) and Celecoxib (171.6 pg/mL). Finally, we performed extensive molecular modeling studies to affirm the binding affinity of this class of compounds to the binding pocket of α-amylase and α-glucosidase enzymes. Collectively, our findings indicate that this class of compounds, particularly compound 5a, could be utilized as a lead structure for the development of novel compounds with potential antidiabetic and antioxidant activities. Full article

Inflammation is the main cause of several autoimmune diseases, including type I diabetes, rheumatoid arthritis, bullous pemphigoid, paraneoplastic pemphigoid, and multiple sclerosis. Currently, there is an urgent demand for the discovery of novel anti-inflammatory drugs with potent activity but also safe for long-term application. Toward this aim, the present study reported the design, synthesis, and characterization of a set of novel 1,3-disubstituted-2-thiohydantoins derivatives. The anti-inflammatory activity of synthesized compounds was assessed against murine leukemia cell line (RAW264.7) by evaluating the cytotoxicity activity and their potency to prevent nitric oxide (NO) production. The results revealed that the synthesized compounds possess a considerable cytotoxic activity together with the ability to reduce the NO production in murine leukemia cell line (RAW264.7). Among synthesized compounds, compound 7 exhibited the most potent cytotoxic activity with IC₅₀ of 197.68 μg/mL, compared to celecoxib drug (IC₅₀ value 251.2 μg/mL), and demonstrated a significant ability to diminish the NO production (six-fold reduction). Exploring the mode of action responsible for the anti-inflammatory activity revealed that compound 7 displays a significant and dose-dependent inhibitory effect on the expression of pro-inflammatory cytokines IL-1β. Furthermore, compound 7 demonstrated the ability to significantly reduce the expression of the inflammatory cytokines IL-6 and TNF-α at 50 μg/mL, as compared to Celecoxib. Finally, detailed molecular modelling studies indicated that compound 7 exhibits a substantial binding affinity toward the binding pocket of the cyclooxygenase 2 enzyme. Taken together, our study reveals that 1,3-disubstituted-2-thiohydantoin could be considered as a promising scaffold for the development of potent anti-inflammatory agents. Full article

Thiohydantoin and quinolone derivatives have attracted researchers’ attention because of a broad spectrum of their medical applications. The aim of our research was to synthesize and analyze the antimicrobial properties of novel 2-thiohydantoin and 2-quinolone derivatives. For this purpose, two series of hybrid compounds were synthesized. Both series consisted of 2-thiohydantoin core and 2-quinolone derivative ring, however one of them was enriched with an acetic acid group at N3 atom in 2-thiohydantoin core. Antibacterial properties of these compounds were examined against bacteria: Staphylococcus aureus, Bacillus subtilis, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. The antimicrobial assay was carried out using a serial dilution method to obtain the MIC. The influence of blue light irradiation on the tested compounds was investigated. The relative yield of singlet oxygen (¹O₂*, ¹Δ_g) generation upon excitation with 420 nm was determined by a comparative method, employing perinaphthenone (PN) as a standard. Antimicrobial properties were also investigated after blue light irradiation of the suspensions of the hybrids and bacteria placed in microtitrate plates. Preliminary results confirmed that some of the hybrid compounds showed bacteriostatic activity to the reference Gram-positive bacterial strains and a few of them were bacteriostatic towards Gram-negative bacteria, as well. Blue light activation enhanced bacteriostatic effect of the tested compounds. Full article

Five new thiohydantoin derivatives (1–5) were isolated from the rhizomes of Lepidium meyenii Walp. NMR (¹H and ¹³C NMR, ¹H−¹H COSY, HSQC, and HMBC), HRESIMS, and ECD were employed for the structure elucidation of new compounds. Significantly, the structure of compound 1 was the first example of thiohydantoins with thioxohexahydroimidazo [1,5-a] pyridine moiety. Additionally, compounds 2 and 3 possess rare disulfide bonds. Except for compound 4, all isolates were assessed for neuroprotective activities in corticosterone (CORT)-stimulated PC12 cell damage. Among them, compound (−)-3 exhibited moderate neuroprotective activity (cell viability: 68.63%, 20 μM) compared to the positive control desipramine (DIM) (cell viability: 88.49%, 10 μM). Full article

In this work, the synthesis of thiohydantoins from l-amino acids and isothiocyanates was studied, using a high purity method based on the Edman cycle. This process, expected to occur through the Michael addition to a series of 1,4-naphthoquinone derivatives did not lead to the expected final product, rather leading to a colored mixture of compounds, where EPR spectra showed that some of them presented unpaired electrons, indicating that an electron transfer pathway was also involved in the reaction mixture. Detected organic radicals proved to be stable albeit with the use of different experimental conditions. Voltammetric results indicated that the reactions led to the formation of electroactive species, probably derived by homogeneous electron transfer between the reactive quinone moieties and the oxidizable urea functions within the hydantoin species. Full article

Very recently, we have reported the synthesis and evaluation of biological properties of new merocyanine dyes composed of triphenylamine moiety, π-aromatic spacer, and rhodanine/2-thiohydantoin-based moiety. Interestingly, 2-thiohydantoin has never been studied before as an electron-accepting/anchoring group for the dye-sensitized solar cells (DSSCs). In the presented study, we examined the applicability of 2-thiohydantoin, an analog of rhodanine, in DSSC technology. The research included theoretical calculations, electrochemical measurements, optical characterization, and tests of the solar cells. As a result, we proved that 2-thiohydantoin might be considered as an acceptor/anchoring group since all the compounds examined in this study were active. The most efficient device showed power conversion efficiency of 2.59%, which is a promising value for molecules of such a simple structure. It was found that the cells’ performances were mainly attributed to the dye loading and the ICT molecular absorption coefficients, both affected by the differences in the chemical structure of the dyes. Moreover, the effect of the aromatic spacer size and the introduction of carboxymethyl co-anchoring group on photovoltaic properties was observed and discussed. Full article

Hydantoins and their sulfur containing analogues, thiohydantoins, are cyclic ureides that have attracted huge attention ever since their discovery. Most of them are biologically active compounds and several points of structural diversity have made them very synthetically attractive. Although substituents can be introduced to the hydantoin nucleus, most substituted hydantoins are synthesized from substrates already containing these groups, while forming the hydantoin nucleus. This is a common route to the synthesis of hydantoins and one of them is employed in this study. A series of 3-allyl-2-thiohydantoins is synthesized from various α-amino acids in a reaction with allyl isothiocyanate. The substitution of the acquired thiohydantoin depends on the structure of the starting α-amino acid. The residual group of the α-amino acid becomes the substituent at the C5-position, while N-monosubstituted amino acids give rise to a substituent in the N1-position. The reaction is carried out in a two-step process and the reaction conditions generally depend on the nature of the amino acid itself. All thiohydantoins are obtained in a good yield and fully characterized by NMR and IR spectroscopy, as well as X-ray crystallography. Full article

The preparation of 5-methylene-thiohydantoins using solid-phase synthesis is reported in this paper. After sulfonylation of immobilized Ser (t-Bu)-OH with 4-nitrobenzenesulfonyl chloride followed by alkylation with various bromoketones, the 4-Nos group was removed and the resulting polymer-supported α-acylamino ketones reacted with Fmoc-isothiocyanate. Cleavage of the Fmoc protecting group was followed by the spontaneous cyclative cleavage releasing the 5-methylene-thiohydantoin derivatives from the polymer support. Reduction with triethylsilane (TES) yielded the corresponding 5-methyl-thiohydantoins. When Fmoc-isothiocyanate was replaced with alkyl isothiocyanates, the trifluoroacetic acid (TFA) mediated cleavage from the polymer support, which was followed by the cyclization reaction and the imidazo[2,1-b]thiazol-4-iums were obtained. Their conversion in deuterated dimethylsulfoxide led to imidazole-2-thiones. Full article

The 41 novel acylthiourea derivatives with hydantoin were synthesized in moderate to excellent yields by using 5-(4-aminophenyl)- and 5-(4-aminobenzyl)-hydantoin or 5-(4-aminobenzyl)-thiohydantoin as raw materials and characterized by IR, ¹H NMR spectra and elementary analysis. The preliminary bioassay showed that these compounds exhibit certain selectively herbicidal activities with the 91%, 94% and 87% inhibition rates of 7l, 8o and 8p against B. campestris, 100%, 100% and 95% efficacy against B. campestris in a greenhouse test, respectively. 7a, 7b, 7c and 7d exhibited 74%, 79%, 79% and 71% inhibition rates against F. oxysporum, respectively. Full article

The sequential sulfonylation/desulfination reactions of 5-benzylthiohydantoin with excess arylsulfonyl chlorides in the presence of triethylamine have been developed to afford a wide range of 5-arylidene thiohydantoin derivatives in moderate to excellent yields. A plausible sulfonylation/desulfination mechanism was proposed. The bioassay showed that these compounds exhibit certain fungicidal activities with the 71.9% inhibition rate of 2K against B. cinerea, and 57.6% inhibition rate of 2m against A. solani, respectively. Full article