Effect of a thiohydantoin salt derived from l-Arginine on Leishmania amazonensis and infected cells: Insights from biological effects to molecular docking interactions.

Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania and is responsible for more than 1 million new cases and 70,000 deaths annually worldwide. Treatment has high costs, toxicity, complex and long administration time, several adverse effects, and drug-resistant strains, therefore new therapies are urgently needed. Synthetic compounds have been highlighted in the medicinal chemistry field as a strong option for drug development against different diseases. Organic salts (OS) have multiple biological activities, including activity against protozoa such as Leishmania spp. This study aimed to investigate the in vitro leishmanicidal activity and death mechanisms of a thiohydantoin salt derived from l-arginine (ThS) against Leishmania amazonensis. We observed that ThS treatment inhibited promastigote proliferation, increased ROS production, phosphatidylserine exposure and plasma membrane permeabilization, loss of mitochondrial membrane potential, lipid body accumulation, autophagic vacuole formation, cell cycle alteration, and morphological and ultrastructural changes, showing parasites death. Additionally, ThS presents low cytotoxicity in murine macrophages (J774A.1), human monocytes (THP-1), and sheep erythrocytes. ThS in vitro cell treatment reduced the percentage of infected macrophages and the number of amastigotes per macrophage by increasing ROS production and reducing TNF-α levels. These results highlight the potential of ThS among thiohydantoins, mainly related to the arginine portion, as a leishmanicidal drug for future drug strategies for leishmaniasis treatment. Notably, in silico investigation of key targets from L. amazonensis, revealed that a ThS compound from the l-arginine amino acid strongly interacts with arginase (ARG) and TNF-α converting enzyme (TACE), suggesting its potential as a Leishmania inhibitor.

In vitro anti-breast cancer study of hybrid cinnamic acid derivatives bearing 2-thiohydantoin moiety.

Aim: To synthesize new hybrid cinnamic acids (10a, 10b and 11) and ester derivatives (7, 8 and 9) and investigate their anti-breast cancer activities.Materials & methods: Compounds 7-11 were evaluated (in vitro) for their cytotoxic activities against the MCF-7 cell line. A flow cytometry examination was performed. Protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2), topoisomerase II and caspase-9 were measured by qRT-PCR. Molecular docking studies were conducted.Results: Several components were discovered to be active, mainly component 11, which induced arrest in the cell cycle at phase S, greatly decreased the expression of Nrf2 and topoisomerase II; and upregulated the expression of caspase-9.Conclusion: The newly thiohydantoin-cinnamic acid hybrids can contribute to creating promising candidates for cancer drugs.

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DMF-DMA catalyzed Synthesis, molecular docking, in-vitro, in-silico design, and binding free energy studies of novel thiohydantoin derivatives as antioxidant and antiproliferative agents targeting EGFR tyrosine kinase and aromatase cytochrome P450 enzyme.

A set of novels 2-thiohydantoin derivatives were synthesized and enaminone function was discussed at position 5 using DMFDMA catalyst which result in formation of pyrazole, isoxazole, benzoxazepine by using reagents such as hydrazine, hydroxylamine and 2-aminothiophenol. These newly synthesized compounds were evaluated for their antioxidant and antiproliferative activity. In vitro studies on the effect of 2-thiohydantoin on scavenging 2,2-diphenyl-1-picrylhydrazyl radical (DPPH•) confirmed the free radical scavenging and antioxidant activity of 2-thiohydantoin. The synthesized compounds show significant antioxidant activity. The in vitro antitumor activity of 2-thiohydantoin on MCF7 (breast) and PC3 cells (prostate) was evaluated using MTT assay. Some of the synthesized compounds show significant to moderate antiproliferative properties compared to reference drug erlotinib. Among all, compound 4a exhibit potent antitumor properties against MCF7 and PC3 cancer cell lines with IC50 = 2.53 ± 0.09 /ml & with IC50 = 3.25 ± 0.12 µg/ml respectively and has potent antioxidant activity with IC50 = 10.04 ± 0.49 µg/ml.

Therapeutic potential of hydantoin and thiohydantoin compounds against Schistosoma mansoni: An integrated in vitro, DNA, ultrastructural, and ADMET in silico approach.

The study aimed to conduct in vitro biological assessments of hydantoin and thiohydantoin compounds against mature Schistosoma mansoni worms, evaluate their cytotoxic effects and predict their pharmacokinetic parameters using computational methods. The compounds showed low in vitro cytotoxicity and were not considered hemolytic. Antiparasitic activity against adult S. mansoni worms was tested with all compounds at concentrations ranging from 200 to 6.25 µM. Compounds SC01, SC02, and SC03 exhibited low activity. Compounds SC04, SC05, SC06 and SC07 caused 100 % mortality within 24 h of incubation at a concentration of 100 and 200 µM. Thiohydantoin SC04 exhibited the highest activity, resulting in 100 % mortality after 24 h of incubation at a concentration of 50 µM and IC50 of 28 µM. In the ultrastructural analysis (SEM), the compound SC04 (200 µM) induced integumentary changes, formation of integumentary blisters, and destruction of tubercles and spicules. Therefore, the SC04 compound shows promise as an antiparasitic against S. mansoni.

Synthesis and Identification of Heterobivalent Anticancer Compounds Containing Urea and 5-Arylidene-2-Thiohydantoin Motifs.

Urea and thiohydantoin are among the important privileged structures for drug discovery. We have developed a synthetic approach to the high-throughput synthesis of the heterobivalent compounds containing both urea and 5-arylidene-2-thiohydantoin functional groups. This synthetic methodology was applied to the synthesis of a mixture-based library containing a total of 5280 compounds in a positional scanning format. The library was screened for its antiproliferative activity against cancer cells using a tetrazolium dye (MTT) based assay. Deconvolution of the library identified six hit compounds exhibiting moderate inhibitory potency against cancer cell proliferation.

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.

One Pot Synthesis and Biological Activity Studies of New Spirooxindoles.

This article reports one-pot synthesis of ten novel spirooxindoles using 5-methyl-2-thiohydantoin, isatin derivatives, and malononitrile in good to high yields (65-90 %). The structures of the synthesized compounds were deduced by 1H-NMR, 13C NMR, FT-IR, and Mass spectral data. The antibacterial activity of the compounds was evaluated against two Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) and two Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) based on the Kirby-Bauer method. According to the obtained data, the synthesized compounds show more activity against Gram-positive bacteria than Gram-negative bacteria. Also, the antioxidant activity of these compounds was measured using the DPPH radical scavenging test method, which showed good to excellent activity (59.65-94.03 %). Among them, the chlorinated derivatives (4 f-j) exhibited more antioxidant activity (84.85-94.03 %) than the other compounds (4 a-e) (56.65-74.4 %) and even ascorbic acid as a standard antioxidant compound (82.3 %).

Highly sensitive fluorescence turn-OFF and reversible chemical sensor for Hg2+ ion based on pyrene appended 2-thiohydantoin.

A novel fluorometric chemical sensor (PY-2TH) based on 2-thiohydantoin (2TH) in conjugation with pyrene (PY) was designed by facile one-pot Knoevenagel condensation reaction and explored for the sensitive and selective detection of Hg2+ ion in solution and solid state methods. Different analytical techniques like NMR and LC-MS concomitantly confirmed the structure of PY-2TH. Absorption and emission studies demonstrate positive solvatochromic effects indicating intramolecular charge transfer in polar solvents. PY-2TH exhibits unprecedented selectivity for detecting Hg2+ ions in tetrahydrofuran (THF) through turn-OFF fluorescence with 90% decrease in the emission intensity with a limit of detection (LOD) of ∼4.4 ppb. The mechanistic investigation through NMR and optical studies confirm the formation of a 2:1 complex between PY-2TH and Hg2+. Thin films of PY-2TH exhibits the J-aggregate formation in the solid state leading to a shift in the emission towards the near-infrared region. Further, we have demonstrated the applicability of PY-2TH for detection of Hg2+ ions and fluorescence imaging in live Zebrafish larvae and the toxicological effects are explored. Cytotoxic evaluation on Zebrafish larval cells revealed that PY-2TH is found to be non-toxic. Detailed analysis demonstrate the potential of PY-2TH for ultra-sensitive Hg2+ ion detection and removal in aqueous environments, highlighting its applicability for identification of metal contamination in live organisms and environmental toxicity.

Design, Synthesis, and Antifungal/Antioomycete Activity of Thiohydantoin Analogues Containing Spirocyclic Butenolide.

Novel fungicidal agents were designed based on the combination of two privileged scaffolds, thiohydantoin and spirocyclic butenolide, which are widely found in natural products. The synthesized compounds were characterized by 1H NMR, 13C NMR, and high-resolution electrospray ionisation mass spectrometry. The in vitro antioomycete activity evaluation showed that most of the compounds exhibited excellent inhibitory activities against different developmental stages in the life cycle of pathogenic oomycete Phytophthora capsici. Compound 5j could inhibit the mycelial growth, sporangium production, zoospore release, and cystospore germination significantly with EC50 values of 0.38, 0.25, 0.11, and 0.026 µg/mL, respectively. The in vivo antifungal/antioomycete bioassay results revealed that the series of compounds generally showed outstanding control efficacies against the pathogenic oomycete Pseudoperonospora cubensis, and compounds 5j, 5l, 7j, 7k, and 7l possessed broad-spectrum antifungal activities against the test phytopathogens. The in vivo protective and curative efficacies against P. capsici of the representative compound 5j were excellent, which were better than those of azoxystrobin. More prominently, 5j significantly promoted the biomass accumulation of the root system and reinforced the cell wall by callose deposition. The pronounced upregulation of immune response-related genes indicated that the active oomycete inhibitor 5j also functioned as a plant elicitor. Transmission electron microscopy observation and the enzyme activity test demonstrated that the mechanism of action of 5j was to bind to the pivotal protein, complex III on the respiratory chain, which resulted in a shortage of energy supply. Molecular docking results exhibited that compound 5j appropriately matched with the Qo pocket and had no interaction with the most commonly mutated site Gly-142, which may be of significant benefit in Qo fungicide resistance management. Compound 5j showed great advantages and potential in oomycete control, resistance management, and induction of disease resistance. A further investigation of 5j with a unique structure might have direct implications for the creation of novel oomycete inhibitors against plant-pathogenic oomycetes.

15,15-Diphenyl-2,3,4,5,6,8,9,11,12-octa-hydro-imidazo[2,1-h][1,4,12]trioxa[7]thia-[9]azacyclo-tetra-decin-14(15H)-one.

The title mol-ecule, C23H26N2O4S, adopts a cup-shaped conformation. In the crystal, layers lying parallel to the ab plane are formed by C-H⋯O hydrogen bonds and C-H⋯π(ring) inter-actions. The layers stack along the c-axis direction through normal van der Waals inter-actions.

Study on Molecular Anti-tumor Mechanism of 2-Thiohydantoin Derivative based on Molecular Docking and Bioinformatic Analyses.

OBJECTIVE: Several methods for synthesizing 2-thiohydantoin derivatives have been devised and exploited, and they have found widespread application as antioxidants, antimicrobials, antivirals, and anticancer agents. As a result, we tried to understand the underlying processes of the 2- thiohydantoin derivative's anti-LIHC activity. METHODS: We predicted the anticancer mechanism of N-(4-oxo-5-(2-oxo-2-(p-tolylamino)ethyl)-3- phenyl-2-thioxoimidazolidin-1-yl)benzamide as a derivative of 2-thiohydantoin by utilizing molecular docking and molecular dynamic simulation. Furthermore, based on the results of molecular dynamic modelling, we employed bioinformatics to anticipate the immunotherapy of this molecule in the tumor microenvironment (TME) of Liver Hepatocellular Carcinoma (LIHC) patients. Next, we examined how this derivative affected proliferation, cell cycle progression, reactive oxygen species production, and apoptosis in HepG2 cancer cells. RESULTS: Substantially, our investigation revealed that the IC50 value was 2.448 µM and that it arrested the cell cycle of HepG2 in the S phase. Furthermore, molecular docking and dynamics studies revealed a worthy interaction of this compound with AKT1 and CDK2 proteins. Considerably, AKT1 and CDK2 have negative affinity energies of -10.4 kcal/mol and -9.6 kcal/mol, respectively. Several bioinformatic tools were used in this investigation to provide insight into the future clinical application of this derivative as a novel candidate to target immune cells such as macrophages, neutrophils, eosinophils, and CD8+ T cells. CONCLUSION: The relevance of this 2-thiohydantoin derivative was demonstrated by our experimental tests, docking studies, and bioinformatics analysis, and it may be investigated as a lead molecule for anticancer medicines, notably as AKT1 and CKD2 inhibitors.

Electronic effect-dependent intramolecular non-covalent interactions on the activity of 4,4-dimethylimidazolidin-2-one pharmacophore-based androgen receptor antagonists.

Because androgen receptor (AR) signalling is important for the development and progression of prostate cancer (PC), AR antagonists are utilized in clinical practices to treat PC and are referred to as androgen deprivation therapy (ADT). However, continued administration of AR antagonists often results in the development of resistance, known as castration-resistant prostate cancer (CRPC). Despite castration, it has been demonstrated that AR signalling continues to be fundamental to tumour growth. In this regard, a series of readily synthesizable 4,4-dimethylimidazolidine-2-one pharmacophore-based AR antagonists (FAR01-FAR11) were designed and synthesized. Androgen-dependent LNCaP PC cell line was used to test the AR-antagonist activity of these compounds in vitro and compared with the U.S. Food and Drug Administration (FDA) approved second-generation enzalutamide. In our previous work, rigid thiohydantoin pharmacophore in enzalutamide is replaced by the flexible 4,4-dimethylimidazolidin-2-one. In order to improve the flexibility further, one methylene group is introduced between the pharmacophore and one of the aromatic ring. Despite the fact that the amide functional group is a crucial characteristic for building AR antagonists, this class of molecules lacks one. FAR06 has the exact same activity as enzalutamide (IC50 : 0.782 µM) with an IC50 value of 0.801 µM among the series of compounds.

Development of Novel 1,3-Disubstituted-2-Thiohydantoin Analogues with Potent Anti-Inflammatory Activity; In Vitro and In Silico Assessments.

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-1ß. 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.

Preliminary Studies of Antimicrobial Activity of New Synthesized Hybrids of 2-Thiohydantoin and 2-Quinolone Derivatives Activated with Blue Light.

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*, 1Δg) 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.

Bonding performance of a thiohydantoin-methacrylate monomer on noble metal alloys.

This study assessed the effect of a primer containing 10-methacryloyloxydecyl-(2-thiohydantoin-4-yl)propionate (MDTHP) on the bonding of noble metal alloys to an acrylic resin. Three noble metal alloys were selected as adherends, and V-Primer containing 6-(4-vinylbenzyl-n-propyl)amino-1,3,5-triazine-2,4-dithione was used as a comparative control. The disk specimens of each noble metal alloy were wet-ground and divided into three conditions: specimens primed with MDTHP primer or V-Primer, and specimens without priming. An acrylic resin was bonded to each specimen, and the specimens were performed the shear bond test. The MDTHP primer showed higher shear bond strength than the V-Primer for all specimens. X-ray photoelectron spectroscopic analysis showed that MDTHP was adsorbed on the Au-Pt-Pd alloy surface even after acetone cleaning. MDTHP binds not only with Cu but also with Au and Ag, promoting the bond strength of noble metal alloys. The effectiveness of MDTHP on dental noble metal alloys was suggested.

Design, synthesis and biological evaluation of novel thiohydantoin derivatives as potent androgen receptor antagonists for the treatment of prostate cancer.

Prostate cancer (PC) is the most common malignancy in men worldwide. Here, two series of novel thiohydantoin derivatives of enzalutamide as potent androgen receptor (AR) antagonists were designed and synthesized. Among them, compound 31c was identified as an AR antagonist which is 2.3-fold more potent than enzalutamide. Molecular docking studies were performed to explain the improved potency of 31c at AR. In cell proliferation assays, 31c exhibited similar anti-proliferative activities with enzalutamide against hormone sensitive LNCaP cells and AR-overexpressing LNCaP/AR cells. These data indicate that 31c can be a good lead compound for further structure optimization for the treatment of prostate cancer.

5-[(1,3-Dimethyl-5-oxo-2-sulfanylideneimidazolidin-4-yl-idene)amino]-2-methyl-isoindoline-1,3-dione.

The title N,N-di-methyl-thio-hydantoin containing an N-methyl-ated pthalimide group, C14H12N4O3S, arose from an unexpected reaction in a deep eutectic di-methyl-thio-urea-tartaric acid solvent system. The mean planes of the ring systems are twisted at an angle of 73.84 (17)°. In the crystal, weak C-H⋯O hydrogen bonds connect the mol-ecules.

Adhesive bonding of noble metals with a thiohydantoin primer.

OBJECTIVE: The purpose of this study was to assess the effects of an experimental primer containing acetone solution and a sulfur-containing functional monomer, 10-methacryloyloxydecyl-(2-thiohydantoin-4-yl)propionate (MDTHP), on the bonds between noble metals and acrylic resin. METHODS: The experimental primer used as the control for comparison consisted of 6-(4-vinylbenzyl-n-propyl)amino-1,3,5-triazine-2,4-dithione (VBATDT) in acetone. These primers were prepared as equimolar functional monomers (0.1 mol%). A self-polymerizing acrylic resin initiated with tri-n-butylborane (TBB) was used as the luting agent. Four elemental metal disks (silver, copper, palladium, and gold) were used as adherend specimens. All the disks were wet-ground with silicon carbide paper (#1500). Bonding reactions were performed on 12 combinations of the four metals, and the disks were either primed with MDTHP or VBATDT or were unprimed (control). Shear bond strengths were determined pre- and post-thermocycling (5-55 °C, dwell time 60 s, 20,000 cycles). The results were statistically analyzed via a non-parametric test (α = 0.05). RESULTS: The post-thermocycling shear bond strengths of the MDTHP primer were as follows (median, n = 11): 13.2 MPa on silver, 25.9 MPa on copper, 4.1 MPa on palladium, and 11.3 MPa on gold. The MDTHP primer showed higher post-thermocycling shear bond strength on all the four metals. Additionally, on silver and copper, the MDTHP bond strengths were higher than on the other metals. SIGNIFICANCE: Within the limitation of current of experimental setting, the MDTHP compound may be applicable as a functional monomer for bonding noble metal alloys.

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.