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.

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.

Macathiohydantoin L, a Novel Thiohydantoin Bearing a Thioxohexahydroimidazo [1,5-a] Pyridine Moiety from Maca (Lepidium meyenii Walp.).

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).

A Novel N-Tert-Butyl Derivatives of Pseudothiohydantoin as Potential Target in Anti-Cancer Therapy.

Tumors are currently more and more common all over the world; hence, attempts are being made to explain the biochemical processes underlying their development. The search for new therapeutic pathways, with particular emphasis on enzymatic activity and its modulation regulating the level of glucocorticosteroids, may contribute to the development and implementation of new therapeutic options in the treatment process. Our research focuses on understanding the role of 11ß-HSD1 and 11ß-HSD2 as factors involved in the differentiation and proliferation of neoplastic cells. In this work, we obtained the 9 novel N-tert-butyl substituted 2-aminothiazol-4(5H)-one (pseudothiohydantoin) derivatives, differing in the substituents at C-5 of the thiazole ring. The inhibitory activity and selectivity of the obtained derivatives in relation to two isoforms of 11ß-HSD were evaluated. The highest inhibitory activity for 11ß-HSD1 showed compound 3h, containing the cyclohexane substituent at the 5-position of the thiazole ring in the spiro system (82.5% at a conc. 10 µM). On the other hand, the derivative 3f with the phenyl substituent at C-5 showed the highest inhibition of 11ß-HSD2 (53.57% at a conc. of 10 µM). A low selectivity in the inhibition of 11ß-HSD2 was observed but, unlike 18ß-glycyrrhetinic acid, these compounds were found to inhibit the activity of 11ß-HSD2 to a greater extent than 11ß-HSD1, which makes them attractive for further research on their anti-cancer activity.

A critical update on the strategies towards modulators targeting androgen receptors.

Prostate cancer is the most common carcinoma of the male urinary system in developed countries. Androgen deprivation therapy has been commonly used in the treatment of prostate cancer for decades, but most patients will inevitably develop into more aggressive castration-resistant prostate cancer. Therefore, novel strategies are urgent to address this resistance mechanism. In this review, we discussed some new strategies for targeting androgen receptors through degradation pathways as potential treatments for prostate cancer.

Synthesis and biological activity of 5-aryliden-2-thiohydantoin S-aryl derivatives.

Three new and complementary approaches to S-arylation of 2-thiohydantoins have been developed: copper-catalyzed cross coupling with either arylboronic acids or aryl iodides under mild conditions, or direct nucleophilic substitution in activated aryl halides. For 38 diverse compounds, reaction yields for all three methods have been determined. Selected by molecular docking, they have been tested on androgen receptor activation, and p53-Mdm2 regulation, and A549, MCF7, VA13, HEK293T, PC3, LnCAP cell lines for cytotoxicity, Two of them turned out to be promising as androgen receptor activators (likely by allosteric regulation), and another one is shown to activate the p53 cascade. It is hoped that 2-thiohydantoin S-arylidenes are worth further studies as biologically active compounds.

Design and synthesis of biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety as novel antibacterial agents against Gram-positive bacteria.

Novel biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety were designed, synthesized and evaluated for their antibacterial activity. The key compounds 7 and 9 were synthesized by the knoevenagel condensation of intermediate aldehyde 5 with rhodanine derivatives 6a-6b. The preliminary study showed that compounds 7, 9 and 10e exhibited potent antibacterial activity with MIC values of 0.125 µg/mL against S. aureus, MRSA, MSSA, LREF and VRE pathogens, using linezolid and radezolid as the positive controls. The most promising compound 10e exhibited potent antibacterial activity against tested clinical isolates of MRSA, MSSA, VRE and LREF with MIC values in the range of 0.125-0.5 µg/mL, and the potency of 10e against clinical isolates of LREF was 64-fold higher than that of linezolid. Moreover, compound 10e was non-cytotoxic with an IC50 value of 91.04 µM against HepG2 cell. Together, compound 10e might serve as a novel antibacterial agent for further investigation.

Thiohydantoin and Hydantoin Derivatives from the Roots of Armoracia rusticana and Their Neurotrophic and Anti-neuroinflammatory Activities.

Two new thiohydantoins (1 and 3) and three new hydantoins (2, 4, and 5) along with three known compounds (6-8) were isolated from roots of horseradish. Physical data analysis including NMR (1H and 13C NMR, 1H-1H COSY, HSQC, and HMBC), HRESIMS, and ECD were employed for structure elucidation of the new compounds 1-5. Potential neuroprotective effects of all compounds (1-8) on nerve growth factor (NGF) induction in C6 glioma were also evaluated. Among these compounds, 1b and 2a exhibited potent NGF secretion stimulation activities (NGF secretion levels: 153.59 ± 5.44% and 141.99 ± 5.21%, respectively). Their anti-neuroinflammatory activities were also assessed based on their inhibitory effects on nitric oxide (NO) production in lipopolysaccharide-stimulated murine microglia. Compound 7 marginally inhibited NO production with an IC50 value of 32.6 µM.

Design, synthesis and evaluation of phthalazinone thiohydantoin-based derivative as potent PARP-1 inhibitors.

Two new series of compounds were designed and synthesized as potent PARP-1 inhibitors. These compounds were evaluated for PARP-1 enzyme and cellular inhibitory activities. All efforts lead to the identification of 9k (named as LG-12) with efficient potency both for PARP-1 and BRCA1 deficient MDA-MB-436 cells. Additionally, the novel PARP-1 inhibitor LG-12 is an efficient chemosensitizer, which could potentiate the anti-cancer effect of TMZ. Our data presented herein provide a comprehensive preclinical in vitro evaluation of the potential therapeutic efficacy and potency of chemotherapeutic agent-PARP-1 inhibitor combinations for LG-12. The combined results indicated that LG-12 could be a promising candidate for further study.

Small-molecule binding of the axin RGS domain promotes ß-catenin and Ras degradation.

Both the Wnt/ß-catenin and Ras pathways are aberrantly activated in most human colorectal cancers (CRCs) and interact cooperatively in tumor promotion. Inhibition of these signaling may therefore be an ideal strategy for treating CRC. We identified KY1220, a compound that destabilizes both ß-catenin and Ras, via targeting the Wnt/ß-catenin pathway, and synthesized its derivative KYA1797K. KYA1797K bound directly to the regulators of G-protein signaling domain of axin, initiating ß-catenin and Ras degradation through enhancement of the ß-catenin destruction complex activating GSK3ß. KYA1797K effectively suppressed the growth of CRCs harboring APC and KRAS mutations, as shown by various in vitro studies and by in vivo studies using xenograft and transgenic mouse models of tumors induced by APC and KRAS mutations. Destabilization of both ß-catenin and Ras via targeting axin is a potential therapeutic strategy for treatment of CRC and other type cancers activated Wnt/ß-catenin and Ras pathways.

Convenient Synthesis of Thiohydantoins, Imidazole-2-thiones and Imidazo[2,1-b]thiazol-4-iums from Polymer-Supported α-Acylamino Ketones.

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.

Design, synthesis, and biological evaluation of deuterated apalutamide with improved pharmacokinetic profiles.

A series of deuterated apalutamide were designed and prepared. Compared to its prototype compound 18, deuterated analogues 19 and 21 showed obviously higher plasma concentrations and better PK parameters after oral administration in mice. In rats, N-trideuteromethyl compound 19 displayed 1.8-fold peak concentration (Cmax), and nearly doubled its drug exposure in plasma (AUC0-∞) compared to compound 18. Unsurprisingly, compounds 18 and 19 had similar affinity for AR in vitro. In summary, the deuteration strategy could obviously improve PK parameters of apalutamide.

Synthesis and biological evaluation of 3-substituted 5-benzylidene-1-methyl-2-thiohydantoins as potent NADPH oxidase (NOX) inhibitors.

We report the synthesis of novel 3-substituted 5-benzylidene-1-methyl-2-thiohydantoins 3, and their biological evaluation using NADPH oxidase (NOX) 1 and 4. Based on structural and pharmacophore analyses of known inhibitors such as hydroxypyrazole 2, we envisioned interesting 2-thiohydantoin compounds, 3-substituted 5-benzylidene-1-methyl-2-thiohydantoins 3 that would be expected to well match the structural features in 2. Efficient synthesis of eighteen target compounds 3 were achieved through the synthetic pathway of 4→11→3, established after consideration of several plausible synthetic pathways. The inhibitory activities of compounds 3 against NOX 1 and 4 were measured, with some of the target compounds showing similar or higher activities compared with reference 2; in particular, compounds 3bz, 3cz, and 3ez were found to be promising inhibitors of both NOX 1 and 4 with modest isozyme selectivities, which highlights the significance of the 2-thiohydantoin substructure for inhibition of NOX 1 and 4. This marks the first time these compounds have been applied to the inhibition of NOX enzymes.

Access to novel imidazo[1,5-a]pyrazine scaffolds by the combined use of a three-component reaction and a base-assisted intramolecular cyclization.

A novel and practical two-step approach to an intriguing class of imidazo[1,5-a]pyrazines with exocyclic C=X (X = CH2, O) bonds is described. The process utilizes a sequential three-component reaction of propargyl amine or aminoester, 1,2-diaza-1,3-dienes and isothiocyanates to furnish functionalized 2-thiohydantoins which are transformed into thiohydantoin-fused tetrahydropyrazines by subsequent regioselective base-promoted cyclization.

Agonist leukadherin-1 increases CD11b/CD18-dependent adhesion via membrane tethers.

Integrin CD11b/CD18 is a key adhesion receptor that mediates leukocyte migration and immune functions. Leukadherin-1 (LA1) is a small molecule agonist that enhances CD11b/CD18-dependent cell adhesion to its ligand ICAM-1. Here, we used single-molecule force spectroscopy to investigate the biophysical mechanism by which LA1-activated CD11b/CD18 mediates leukocyte adhesion. Between the two distinct populations of CD11b/CD18:ICAM-1 complex that participate in cell adhesion, the cytoskeleton(CSK)-anchored elastic elements and the membrane tethers, we found that LA1 enhanced binding of CD11b/CD18 on K562 cells to ICAM-1 via the formation of long membrane tethers, whereas Mn(2+) additionally increased ICAM-1 binding via CSK-anchored bonds. LA1 activated wild-type and LFA1(-/-) neutrophils also showed longer detachment distances and time from ICAM-1-coated atomic force microscopy tips, but significantly lower detachment force, as compared to the Mn(2+)-activated cells, confirming that LA1 primarily increased membrane-tether bonds to enhance CD11b/CD18:ICAM-1 binding, whereas Mn(2+) induced additional CSK-anchored bond formation. The results suggest that the two types of agonists differentially activate integrins and couple them to the cellular machinery, providing what we feel are new insights into signal mechanotransduction by such agents.

A naked-eye chemosensor for fluoride ions: a selective easy-to-prepare test paper.

A new naked-eye chromogenic chemosensor based on 2-thiohydantoin shows high selectivity for fluoride ions and is used to develop a test paper for detection of fluoride ions in the solid state.

Facile synthesis of 5-arylidene thiohydantoin by sequential sulfonylation/desulfination reaction.

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.

Discovery of thiohydantoin based antagonists of androgen receptor with efficient degradation for the treatment of prostate cancer.

Prostate cancer (PC) is one of the most prevalent cancers in men worldwide, and androgen receptor (AR) is a well-validated drug target for the treatment of PC. However, PC often exhibits resistance to AR antagonists over time. Thus, it is urgent to identify novel and effective drugs for PC treatment. A series of novel thiohydantoin based AR antagonists with efficient degradation against AR were designed, synthesized, and evaluated. Based on our previous SAR and further structural optimization, a tool molecule 26h was discovered with dual mechanisms including improved antagonistic activity and potent degradation (AR-fl and AR-V7). Moreover, 26h can also effectively block AR nuclear translocation and inhibit AR/AR-V7 heterodimerization, thereby inhibiting downstream gene transcription. Importantly, 26h displayed potent robust efficacy in LNCaP (TGI: 70.70%) and 22Rv1 (TGI: 78.89%) xenograft models. This provides new design strategies and advantageous potential compounds for the treatment of prostate cancer.

Novel pyrrolidine-thiohydantoins/thioxotetrahydropyrimidinones as highly effective catalysts for the asymmetric Michael addition.

The synthesis of novel organocatalysts consisting of a pyrrolidine moiety and a thiohydantoin or a thioxotetrahydropyrimidinone ring is described. The compound combining the pyrrolidine with the thioxotetrahydropyrimidinone was found to be a highly effective catalyst for the Michael reaction. Low catalyst loadings (1-2.5%) can be employed leading to quantitative yields and excellent stereoselectivities in the reaction between cyclic ketones and nitroolefins.

Microwave assisted synthesis of novel functionalized hydantoin derivatives and their conversion to 5-(Z) arylidene-4H-imidazoles.

2-(Alkyl-1-yl)-1H-imidazol-5(4H)-ones 5a-n were synthesized via nucleophilic substitution of the methylsulfanyl group of the corresponding 2-(methylthio)-1H-imidazol-5(4H)-ones 3a-c with suitably substituted secondary amines. The starting 2-thioxo- imidazolidin-4-ones 2a,2b were prepared by condensation of thiohydantoin and benzo[b]-thiophene-3-carbaldehyde or benzofuran-3-carbaldehyde under microwave irracdiation (MW) conditions. 2-Methylthio derivatives 3a-c were prepared by treatment of 2a-b with methyl iodide in the presence of aqueous sodium hydroxide.