Design, synthesis, and biological evaluation of (thio)urea derivatives as potent Escherichia coli ß-glucuronidase inhibitors.

EcGUS has drawn considerable attention for its role as a target in alleviating serious GIAEs. In this study, a series of 72 (thio)urea derivatives were designed, synthesised, and biologically assayed. The bioassay results revealed that E-9 (IC50 = 2.68 µM) exhibited a promising inhibitory effect on EcGUS, surpassing EcGUS inhibitor D-saccharic acid-1,4-lactone (DSL, IC50 = 45.8 µM). Additionally, the inhibitory kinetic study indicated that E-9 (Ki = 1.64 µM) acted as an uncompetitive inhibitor against EcGUS. The structure-activity relationship revealed that introducing an electron-withdrawing group into the benzene ring at the para-position is beneficial for enhancing inhibitory activity against EcGUS. Furthermore, molecular docking analysis indicated that E-9 has a strong affinity to EcGUS by forming interactions with residues Asp 163, Tyr 472, and Glu 504. Overall, these results suggested that E-9 could be a potent EcGUS inhibitor, providing valuable insights and guidelines for the development of future inhibitors targeting EcGUS.

Crystal structure of 1-(1,3-benzo-thia-zol-2-yl)-3-(4-bromo-benzo-yl)thio-urea.

The chemical reaction of 4-bromo-benzoyl-chloride and 2-amino-thia-zole in the presence of potassium thio-cyanate yielded a white solid formulated as C15H10BrN3OS2, which consists of 4-bromo-benzamido and 2-benzo-thia-zolyl moieties connected by a thio-urea group. The 4-bromo-benzamido and 2-benzo-thia-zolyl moieties are in a trans conformtion (sometimes also called s-trans due to the single bond) with respect to the N-C bond. The dihedral angle between the mean planes of the 4-bromo-phenyl and the 2-benzo-thia-zolyl units is 10.45 (11)°. The thio-urea moiety, -C-NH-C(=S) -NH- fragment forms a dihedral angle of 8.64 (12)° with the 4-bromo-phenyl ring and is almost coplanar with the 2-benzo-thia-zolyl moiety, with a dihedral angle of 1.94 (11)°. The mol-ecular structure is stabilized by intra-molecular N-H⋯O hydrogen bonds, resulting in the formation of an S(6) ring. In the crystal, pairs of adjacent mol-ecules inter-act via inter-molecular hydrogen bonds of type C-H⋯N, C-H⋯S and N-H⋯S, resulting in mol-ecular layers parallel to the ac plane.

Synthesis, characterization, and crystal structures of N,N'-bis-(2-di-alkyl-amino-phen-yl)thio-ureas.

N,N'-Bis[2-(di-methyl-amino)-phen-yl]thio-urea, C17H22N4S (1), and N,N'-bis-[2-(di-ethyl-amino)-phen-yl]thio-urea, C21H30N4S (2), were prepared by the treatment of 1,1'-thio-carbonyl-diimidazole and 2 equivalents of 2-amino-N,N'-di-alkyl-aniline. Both compounds exhibit intra-molecular hydrogen bonds between the N-H(thio-urea) and NR 2 (R = Me, Et) groups. The other N-H bonds face the sulfur atoms of S=C bonds in an adjacent mol-ecule, which forms an inter-molecular inter-action in the packed structure. The structural details match the spectroscopic data acquired from NMR and IR spectroscopy.

Crystal structure, Hirshfeld surface and computational study of 1-(9,10-dioxo-9,10-di-hydroanthracen-1-yl)-3-propano-ylthio-urea.

The title compound, C18H14N2O3S, crystallizes in the ortho-rhom-bic crystal system and Pbca space group. The thio-urea chromophore is planar to an r.m.s deviation of 0.032 Šwith the thiol-ate sulfur atom being the most deviated. Bifurcated N-H⋯O intra-molecular hydrogen bonds result in an S(6) supra-molecular synthon. In the crystal, mol-ecules are linked by N-H⋯O inter-molecular hydrogen-bonding inter-actions and stabilized by C-H⋯π and π-π inter-actions. Hirshfeld surface analysis and fingerprint plot indicate the H⋯H inter-molecular contacts as the highest contributor to the overall surface contacts (38%) and this is supported by the high dispersive and electrostatic inter-action energies.

Polarization Engineering of Covalent Triazine Frameworks for Highly Efficient Photosynthesis of Hydrogen Peroxide from Molecular Oxygen and Water.

Two-electron oxygen photoreduction to hydrogen peroxide (H2 O2 ) is seriously inhibited by its sluggish charge kinetics. Herein, a polarization engineering strategy is demonstrated by grafting (thio)urea functional groups onto covalent triazine frameworks (CTFs), giving rise to significantly promoted charge separation/transport and obviously enhanced proton transfer. The thiourea-functionalized CTF (Bpt-CTF) presents a substantial improvement in the photocatalytic H2 O2 production rate to 3268.1 µmol h-1 g-1 with no sacrificial agents or cocatalysts that is over an order of magnitude higher than unfunctionalized CTF (Dc-CTF), and a remarkable quantum efficiency of 8.6% at 400 nm. Mechanistic studies reveal the photocatalytic performance is attributed to the prominently enhanced two-electron oxygen reduction reaction by forming endoperoxide at the triazine unit and highly concentrated holes at the thiourea site. The generated O2 from water oxidation is subsequently consumed by the oxygen reduction reaction (ORR), thereby boosting overall reaction kinetics. The findings suggest a powerful functional-groups-mediated polarization engineering method for the development of highly efficient metal-free polymer-based photocatalysts.

Synthesis, crystal structure and thermal properties of bis-(1,3-di-cyclo-hexyl-thio-urea-κS)bis(iso-thiocyanato-κN)cobalt(II).

Crystals of the title compound, [Co(NCS)2(C13H24N2S)2], were obtained by the reaction of Co(NCS)2 with 1,3-di-cyclo-hexyl-thio-urea in ethanol. Its crystal structure consists of discrete complexes that are located on twofold rotation axes, in which the CoII cations are tetra-hedrally coordinated by two terminal N-bonded thio-cyanate anions and two 1,3-di-cyclo-hexyl-thio-urea ligands. These complexes are linked via inter-molecular N-H⋯S and C-H⋯S hydrogen bonding into chains, which elongate in the b-axis direction. These chains are closely packed in a pseudo-hexa-gonal manner. The CN stretching vibration of the thio-cyanate anions located at 2038 cm-1 is in agreement with only terminal bonded anionic ligands linked to metal cations in a tetra-hedral coordination. TG-DTA measurements prove the decomposition of the compound at about 227°C. DSC measurements reveal a small endothermic signal before decomposition at about 174°C, which might correspond to melting.

1-{(E)-[4-(4-Hy-droxy-phen-yl)butan-2-yl-idene]amino}-3-phenyl-thio-urea: crystal structure, Hirshfeld surface analysis and computational study.

The title thio-urea derivative, C17H19N3OS, adopts a U-shaped conformation with the dihedral angle between the terminal aromatic rings being 73.64 (5)°. The major twist in the mol-ecule occurs about the ethane bond with the Ci-Ce-Ce-Cb torsion angle being -78.12 (18)°; i = imine, e = ethane and b = benzene. The configuration about the imine bond is E, the N-bound H atoms lie on opposite sides of the mol-ecule and an intra-molecular amine-N-H⋯N(imine) hydrogen bond is evident. In the mol-ecular packing, hydroxyl-O-H⋯S(thione) and amine-N-H⋯O hydrogen bonding feature within a linear, supra-molecular chain. The chains are connected into a layer in the ab plane by a combination of methyl-ene-C-H⋯S(thione), methyl-ene-C-H⋯O(hydrox-yl), methyl-C-H⋯π(phen-yl) and phenyl-C-H⋯π(hy-droxy-benzene) inter-actions. The layers stack without directional inter-actions between them. The analysis of the calculated Hirshfeld surface highlights the presence of weak methyl-C-H⋯O(hydrox-yl) and H⋯H inter-actions in the inter-layer region. Computational chemistry indicates that dispersion energy is the major contributor to the overall stabilization of the mol-ecular packing.

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.

Bifunctional Hydrogen Bond Donor-Catalyzed Diels-Alder Reactions: Origin of Stereoselectivity and Rate Enhancement.

The selectivity and rate enhancement of bifunctional hydrogen bond donor-catalyzed Diels-Alder reactions between cyclopentadiene and acrolein were quantum chemically studied using density functional theory in combination with coupled-cluster theory. (Thio)ureas render the studied Diels-Alder cycloaddition reactions exo selective and induce a significant acceleration of this process by lowering the reaction barrier by up to 7 kcal mol-1 . Our activation strain and Kohn-Sham molecular orbital analyses uncover that these organocatalysts enhance the Diels-Alder reactivity by reducing the Pauli repulsion between the closed-shell filled π-orbitals of the diene and dienophile, by polarizing the π-orbitals away from the reactive center and not by making the orbital interactions between the reactants stronger. In addition, we establish that the unprecedented exo selectivity of the hydrogen bond donor-catalyzed Diels-Alder reactions is directly related to the larger degree of asynchronicity along this reaction pathway, which is manifested in a relief of destabilizing activation strain and Pauli repulsion.

Crystal structure of bis-[µ-N-(η2-prop-2-en-1-yl)piperidine-1-carbo-thio-amide-κ2 S:S]bis-[(thio-cyanato-κN)copper(I)].

The title crystalline compound, [Cu2(NCS)2(C9H16N2)2], was obtained from the reaction of copper(I) thio-cyanate (CuSCN) with (N-prop-2-en-1-yl)piperidine-1-carbo-thio-amide as a chelating and bridging thio-urea ligand in chloro-benzene. The Cu2S2 core of the dimeric mol-ecule is situated on a crystallographic inversion centre. The copper atom is coordinated by a thio-cyanate nitro-gen atom, each sulfur atom of the two thio-urea ligands, and the C=C double bond of the ligand in a distorted tetra-hedral geometry. The dimers are linked by N-H⋯S hydrogen bonds, forming a network extending in two dimensions parallel to (100).

Dihomooxacalix[4]arene-Based Fluorescent Receptors for Anion and Organic Ion Pair Recognition.

Fluorescent dihomooxacalix[4]arene-based receptors 5a-5c, bearing two naphthyl(thio)ureido groups at the lower rim via a butyl spacer, were synthesised and obtained in the cone conformation in solution. The X-ray crystal structures of 1,3- (5a) and 3,4-dinaphthylurea (5b) derivatives are reported. Their binding properties towards several anions of different geometries were assessed by 1H-NMR, UV-Vis absorption and fluorescence titrations. Structural and energetic insights of the naphthylurea 5a and 5b complexes were also obtained using quantum mechanical calculations. The data showed that all receptors follow the same trend, the association constants increase with the anion basicity, and the strongest complexes were obtained with F-, followed by the oxoanions AcO- and BzO-. Proximal urea 5b is a better anion receptor compared to distal urea 5a, and both are more efficient than thiourea 5c. Compounds 5a and 5b were also investigated as heteroditopic receptors for biologically relevant alkylammonium salts, such as the neurotransmitter γ-aminobutyric acid (GABA·HCl) and the betaine deoxycarnitine·HCl. Chiral recognition towards the guest sec-butylamine·HCl was also tested, and a 5:2 selectivity for (R)-sec-BuNH3+·Cl- towards (P) or (M) enantiomers of the inherently chiral receptor 5a was shown. Based on DFT calculations, the complex [(S)-sec-BuNH3+·Cl-/(M)-5a] was indicated as the more stable.

Crystal structure of bis-(N,N'-di-methyl-thio-urea-κS)bis-(thio-cyanato-κN)cobalt(II).

During systematic investigations on the synthesis of coordination polymers with Co(NCS)2 involving different thio-urea derivatives as coligands, crystals of the title compound Co(NCS)2(N,N'-di-methyl-thio-urea)2, or [Co(C3H8N2S)2(NCS)2], were obtained. These crystals were non-merohedric twins and therefore, a twin refinement using data in HKLF-5 format was performed. In the crystal structure of this compound, the CoII cations are coordinated by two N-terminally bonded thio-cyanate anions as well as two S-bonding N,N'-di-methyl-thio-urea mol-ecules, forming two crystallographically independent discrete complexes each with a strongly distorted tetra-hedral geometry. An intricate network of inter-molecular N-H⋯S and C-H⋯S hydrogen bonds can be found between the complexes. The thermogravimetric curve of the title compound shows two discrete steps in which all coligand mol-ecules have been emitted, which is also accompanied by partial decomposition of the cobalt thio-cyanate. If the measurement is stopped after the first mass loss, only broad reflections of CoS can be found in the XRPD pattern of the residue, which proves that this compound decomposes completely upon heating. However, at lower temperatures an endothermic signal can be found in the DTA and DSC curve, which corresponds to melting, as proven by thermomicroscopy.

Crystal structure of bis-(tetra-methyl-thio-urea-κS)bis(thio-cyanato-κN)cobalt(II).

In the course of systematic investigations on the synthesis of Co(NCS)2 coordination compounds with different thio-urea ligands, the title compound, [Co(NCS)2(C5H12N2S)2], was obtained. In this compound the CoII cations are coordinated by two crystallographically independent N-bonded thio-cyanate anions and two tetra-methyl-thio-urea ligands into discrete complexes that are located in general positions and show a strongly distorted tetra-hedral geometry. Inter-molecular C-H⋯S hydrogen bonds of different strength can be observed between the discrete complexes, which are connected by pairs of hydrogen bonds into zigzag-like chains that elongate in the b-axis direction. These chains are additionally linked by strong C-H⋯S hydrogen bonds along the a-axis direction, resulting in the formation of layers that are parallel to the ab plane. There is also one weak intra-molecular C-H⋯S hydrogen bond between two neighbouring thio-urea ligands within the complexes. Comparison of the experimental PXRD pattern with that calculated from the single-crystal data prove that a pure phase has been obtained. Thermoanalytical investigations reveal that this compound melts at 364 K and decomposes upon further heating.

2-[Carbamo-thio-yl(2-hy-droxy-eth-yl)amino]-ethyl benzoate: crystal structure, Hirshfeld surface analysis and computational study.

The title di-substituted thio-urea, C12H16N2O3S, has the hy-droxy-lethyl and ethyl benzoate substituents bound to the same amine-N atom, and is twisted, having a (+)syn-clinal conformation with the Namine-C-C-O(hydroxyl, carbon-yl) torsion angles of 49.39 (13) and 59.09 (12)°, respectively; the dihedral angle between the almost planar CN2S core and the pendent benzene ring is 69.26 (4)°. In the crystal, supra-molecular layers propagating in the ac plane are formed via a combination of hydroxyl-O-H⋯S(thione), amine-N-H⋯O(hydroxyl, carbon-yl) hydrogen-bonds. The layers stack along the b axis with inter-digitation of the benzene rings allowing the formation of π-π stacking [inter-centroid separation = 3.8722 (7) Å] and parallel C=O⋯π inter-actions. A computational chemistry study shows the conventional hydrogen bonding in the crystal leads to significant electrostatic stabilization but dispersion terms are also apparent, notably through the inter-actions involving the benzene residue.

3,3-Bis(2-hy-droxy-eth-yl)-1-(4-nitro-benzo-yl)thio-urea: crystal structure, Hirshfeld surface analysis and computational study.

In the title compound, C12H15N3O5S, a tris-ubstituted thio-urea derivative, the central CN2S chromophore is almost planar (r.m.s. deviation = 0.018 Å) and the pendant hy-droxy-ethyl groups lie to either side of this plane. While to a first approximation the thione-S and carbonyl-O atoms lie to the same side of the mol-ecule, the S-C-N-C torsion angle of -47.8 (2)° indicates a considerable twist. As one of the hy-droxy-ethyl groups is orientated towards the thio-amide residue, an intra-molecular N-H⋯O hydrogen bond is formed which leads to an S(7) loop. A further twist in the mol-ecule is indicated by the dihedral angle of 65.87 (7)° between the planes through the CN2S chromophore and the 4-nitro-benzene ring. There is a close match between the experimental and gas-phase, geometry-optimized (DFT) mol-ecular structures. In the crystal, O-H⋯O and O-H⋯S hydrogen bonds give rise to supra-molecular layers propagating in the ab plane. The connections between layers to consolidate the three-dimensional architecture are of the type C-H⋯O, C-H⋯S and nitro-O⋯π. The nature of the supra-molecular association has been further analysed by a study of the calculated Hirshfeld surfaces, non-covalent inter-action plots and computational chemistry, all of which point to the significant influence and energy of stabilization provided by the conventional hydrogen bonds.

Crystal engineering of exemestane to obtain a co-crystal with enhanced urease inhibition activity.

Co-crystallization is a phenomenon widely employed to enhance the physio-chemical and biological properties of active pharmaceutical ingredients (APIs). Exemestane, or 6-methyl-ideneandrosta-1,4-diene-3,17-dione, is an anabolic steroid used as an irreversible steroidal aromatase inhibitor, which is in clinical use to treat breast cancer. The present study deals with the synthesis of co-crystals of exemestane with thio-urea by liquid-assisted grinding. The purity and homogeneity of the exemestane-thio-urea (1:1) co-crystal were confirmed by single-crystal X-ray diffraction followed by thermal stability analysis on the basis of differential scanning calorimetry and thermogravimetric analysis. Detailed geometric analysis of the co-crystal demonstrated that a 1:1 co-crystal stoichiometry is sustained by N-H⋯O hydrogen bonding between the amine (NH2) groups of thio-urea and the carbonyl group of exemestane. The synthesized co-crystal exhibited potent urease inhibition activity in vitro (IC50 = 3.86 ± 0.31 µg ml-1) compared with the API (exemestane), which was found to be inactive, and the co-former (thio-urea) (IC50 = 21.0 ± 1.25 µg ml-1), which is also an established tested standard for urease inhibition assays in vitro. The promising results of the present study highlight the significance of co-crystallization as a crystal engineering tool to improve the efficacy of pharmaceutical ingredients. Furthermore, the role of various hydrogen bonds in the crystal stability is successfully analysed quantitatively using Hirshfeld surface analysis.

Hunig's base catalyzed synthesis of new 1-(2,3-dihydro-1H-inden-1-yl)-3-aryl urea/thiourea derivatives as potent antioxidants and 2HCK enzyme growth inhibitors.

A series of 1-(2,3-dihydro-1H-indan-1-yl)-3-aryl urea/thiourea derivatives (4a-j) have been synthesized from the reaction of 2,3-dihydro-1H-inden-1-amine (2) with various aryl isocyanates/isothiocyanates (3a-j) by using N,N-DIPEA base (Hunig's base) catalyst in THF at reflux conditions. All of them are structurally confirmed by spectral (IR, 1H &13C NMR and MASS) and elemental analysis and screened for their in-vitro antioxidant activity against DPPH and NO free radicals and found that compounds 4b, 4i, 4h &4g are potential antioxidants. The obtained in vitro results were compared with the molecular docking, ADMET, QSAR and bioactivity study results performed for them and identified that the recorded in silico binding affinities were observed in good correlation with the in vitro antioxidant results. The Molecular docking analysis had unveiled the strong hydrogen bonding interactions of synthesized ligands with ARG 160 residue of protein tyrosine kinase (2HCK) enzyme and plays an effective role in its inhibition. Toxicology studies have assessed the potential risks of 4a-j and inferred that all of them were in the limits of potential drugs. The conformational analysis of 4a-j inferred that the urea/thiourea spacer linking 2,3-dihydro-1H-inden-1-amino and substituted aryl units has facilitated all these molecules to effectively bind with ARG 160 amino acid residue present on the α-helix of the protein tyrosine kinase (2HCK) enzyme specifically on chain A of hemopoetic cell kinase. Collectively this study has established a relationship between the antioxidant potentiality and ligands binding with ARG 160 amino acid residue of chain A of 2HCK enzyme to inhibit its growth as well as proliferation of reactive oxygen species in vivo.

Optimization of piperazine-derived ureas privileged structures for effective antiadenovirus agents.

In recent years, human adenovirus (HAdV) infections have shown a high clinical impact in both immunosuppressed and immunocompetent patients. The research into specific antiviral drugs for the treatment of HAdV infections in immunocompromised patients constitutes a principal objective for medicinal chemistry due to the lack of any specific secure drug to treat these infections. In this study, we report a small-molecule library (67 compounds) designed from an optimization process of piperazine-derived urea privileged structures and their biological evaluation: antiviral activity and cytotoxicity. The active compounds selected were further evaluated to gain mechanistic understanding for their inhibition. Twelve derivatives were identified that inhibited HAdV infections at nanomolar and low micromolar concentrations (IC50 from 0.6 to 5.1 µM) with low cytotoxicity. In addition, our mechanistic assays suggested differences in the way the derivatives exert their anti-HAdV activity targeting transcription, DNA replication and later steps in the HAdV replication cycle. Furthermore, eight of the 12 studied derivatives blocked human cytomegalovirus (HCMV) DNA replication at low micromolar concentrations. The data provided herein indicates that the 12 thiourea/urea piperazine derivatives studied may represent potential lead compounds for clinical evaluation and development of new anti-HAdV drugs.

[1,2,3]Triazolo[4,5-d]pyrimidine derivatives incorporating (thio)urea moiety as a novel scaffold for LSD1 inhibitors.

Lysine specific demethylase 1 (LSD1) plays an essential role in maintaining a balanced methylation status at histone tails. Overexpression of LSD1 has been involved in the development of a variety of human diseases, including cancers. Herein, on the basis of our previously developed LSD1 inhibitors, two series of new [1,2,3]triazolo[4,5-d]pyrimidine derivatives incorporating (thio)urea moiety were designed and evaluated for their LSD1 inhibitory abilities, leading to a novel chemical class of LSD1 inhibitors. Among them, compound 31 was found to moderately inhibit LSD1 activity, as well as increase the expression of H3K4me2 at the cellular level. This compound also showed good selectivity against MAO-A/-B, and a panel of kinases such as CDK and BTK. Besides, the MTT assay suggested that the selected compounds could inhibit the proliferation of LSD1-overexpressed cancer cells. Although this class of compounds only showed moderate anti-LSD1 activity in the micromolar range, this work presents a novel chemotype of LSD1 inhibitors with good enzyme selectivity as well as cellular LSD1 inhibitory activity, and could provide a useful template for the development of more potent LSD1 inhibitors for cancer treatment.

Crystal structure of bis-(tetra-methyl-thio-urea-κS)bis-(thio-cyanato-κN)nickel(II).

In the course of our investigations regarding transition-metal thio-cyanates with thio-urea derivatives, the title compound, [Ni(NCS)2(C5H12N2S)2], was obtained. The asymmetric unit consists of one thio-cyanate anion and one tetra-methyl-thio-urea mol-ecule on general positions, as well as one NiII cation that is located on a twofold rotational axis. In this compound, discrete complexes are formed in which the NiII cations are surrounded by two trans-N-bonding thio-cyanate anions as well as two trans-S-bonding tetra-methyl-thio-urea mol-ecules within a distorted square-planar coordination geometry. The discrete complexes are linked by pairs of weak C-H⋯S hydrogen bonds between the thio-cyanate S and one of the tetra-methyl-thio-urea methyl hydrogen atoms into chains along the crystallographic a- and c-axis directions, which are combined into layers parallel to the ac plane. X-ray powder diffraction proves that a pure crystalline phase was obtained and measurements using thermogravimetry and differential thermoanalysis reveal that the compound decomposes at about 408 K, where all tetra-methyl-thio-urea mol-ecules are lost.