Structures of the hydrolase domain of zebrafish 10-formyltetrahydrofolate dehydrogenase and its complexes reveal a complete set of key residues for hydrolysis and product inhibition.

10-Formyltetrahydrofolate dehydrogenase (FDH), which is composed of a small N-terminal domain (Nt-FDH) and a large C-terminal domain, is an abundant folate enzyme in the liver and converts 10-formyltetrahydrofolate (10-FTHF) to tetrahydrofolate (THF) and CO2. Nt-FDH alone possesses a hydrolase activity, which converts 10-FTHF to THF and formate in the presence of ß-mercaptoethanol. To elucidate the catalytic mechanism of Nt-FDH, crystal structures of apo-form zNt-FDH from zebrafish and its complexes with the substrate analogue 10-formyl-5,8-dideazafolate (10-FDDF) and with the products THF and formate have been determined. The structures reveal that the conformations of three loops (residues 86-90, 135-143 and 200-203) are altered upon ligand (10-FDDF or THF) binding in the active site. The orientations and geometries of key residues, including Phe89, His106, Arg114, Asp142 and Tyr200, are adjusted for substrate binding and product release during catalysis. Among them, Tyr200 is especially crucial for product release. An additional potential THF binding site is identified in the cavity between two zNt-FDH molecules, which might contribute to the properties of product inhibition and THF storage reported for FDH. Together with mutagenesis studies and activity assays, the structures of zNt-FDH and its complexes provide a coherent picture of the active site and a potential THF binding site of zNt-FDH along with the substrate and product specificity, lending new insights into the molecular mechanism underlying the enzymatic properties of Nt-FDH.

Cobalt-Catalyzed Decarboxylative 2-Benzoylation of Oxazoles and Thiazoles with α-Oxocarboxylic Acids.

Cobalt-catalyzed decarboxylative cross-coupling of oxazoles and thiazoles with α-oxocarboxylic acids was developed through an sp(2) C-H bond functionalization process. This work represents the first example of cobalt-catalyzed decarboxylative C-H bond functionalization and provides an efficient means of building some important bioactive heteroaryl ketone derivatives.

An azodye-rhodamine-based fluorescent and colorimetric probe specific for the detection of Pd(2+) in aqueous ethanolic solution: synthesis, XRD characterization, computational studies and imaging in live cells.

Azodye-rhodamine hybrid colorimetric fluorescent probe (L) has been designed and synthesized. The structure of L has been established based on single crystal XRD. It has been shown to act as a selective turn-on fluorescent chemosensor for Pd(2+) with >40 fold enhancement by exhibiting red emission among the other 27 cations studied in aqueous ethanol. The coordination features of the species of recognition have been computationally evaluated by DFT methods and found to have a distorted tetrahedral Pd(2+) center in the binding core. The probe (L) has been shown to detect Pd up to 0.45 µM at pH 7.4. Furthermore, the probe can be used to image Pd(2+) in living cells.

Targeting HER-2 over expressed breast cancer cells with 2-cyclohexyl-N-[(Z)-(substituted phenyl/furan-2-yl/thiophene-2-yl)methylidene]hydrazinecarbothioamide.

Cyclohexyl thiosemicarbazone derivatives (C1-14) were synthesized, characterized and evaluated against HER-2 over expressed breast cancer cells. The synthesized compounds were screened in vitro against four breast cancer cell lines; SKBr-3, MCF-7, MDA-MB-468 and MDA-MB-231. All the compounds showed activity against HER-2 over expressed SKBr-3 cells with (IC50 = 25.6 ± 0.07 µM-61.6 ± 0.4 µM). The most active compounds inhibit ALDH⁺ breast cancer stem cells more effectively than the cancer stem cells specific agent Salinomycin. Immunohistochemistry staining also confirmed that these compounds inhibit the expression of HER-2 on SKBr-3 cells. Compound C2 significantly inhibited the cell migration and cell adhesion of breast cancer cell lines. Compound C2 was found to most active compound of this series targeting HER-2 over expressed breast cancer cells.

Cd(2+) Triggered the FRET "ON": A New Molecular Switch for the Ratiometric Detection of Cd(2+) with Live-Cell Imaging and Bound X-ray Structure.

On the basis of the Förster resonance energy transfer mechanism between rhodamine and quinoline-benzothiazole conjugated dyad, a new colorimetric as well as fluorescence ratiometric probe was synthesized for the selective detection of Cd(2+). The complex formation of the probe with Cd(2+) was confirmed through Cd(2+)-bound single-crystal structure. Capability of the probe as imaging agent to detect the cellular uptake of Cd(2+) was demonstrated here using living RAW cells.

Synthesis, in vitro biological activities and in silico study of dihydropyrimidines derivatives.

We describe here the synthesis of dihydropyrimidines derivatives 3a-p, and evaluation of their α-glucosidase enzyme inhibition activities. Compounds 3b (IC50=62.4±1.5 µM), 3c (IC50=25.3±1.26 µM), 3d (IC50=12.4±0.15 µM), 3e (IC50=22.9±0.25 µM), 3g (IC50=23.8±0.17 µM), 3h (IC50=163.3±5.1 µM), 3i (IC50=30.6±0.6 µM), 3m (IC50=26.4±0.34 µM), and 3o (IC50=136.1±6.63 µM) were found to be potent α-glucosidase inhibitors in comparison to the standard drug acarbose (IC50=840±1.73 µM). The compounds were also evaluated for their in vitro cytotoxic activity against PC-3, HeLa, and MCF-3 cancer cell lines, and 3T3 mouse fibroblast cell line. All compounds were found to be non cytotoxic, except compounds 3f and 3m (IC50=17.79±0.66-20.44±0.30 µM), which showed a weak cytotoxic activity against the HeLa, and 3T3 cell lines. In molecular docking simulation study, all the compounds were docked into the active site of the predicted homology model of α-glucosidase enzyme. From the docking result, it was observed that most of the synthesized compounds showed interaction through carbonyl oxygen atom and polar phenyl ring with active site residues of the enzyme.

A novel one-pot green synthesis of dispirooxindolo-pyrrolidines via 1,3-dipolar cycloaddition reactions of azomethine ylides.

A facile synthesis of dispirooxindolopyrrolidines has been accomplished via a one-pot three component 1,3-dipolar cycloaddition reaction. The reaction of azomethine ylides generated in situ from L-phenylalanine and substituted isatins with a series of unusual (E)-2-oxoindolino-3-ylidene acetophenone dipolarophiles in the ionic liquid 1-butyl-3-methylimidazolium bromide [bmim]BF4, furnished the cycloadducts in good yields, with the regioisomers 5a-f being obtained with high selectivity. Furthermore, the recyclability of [bmim]BF4, up to five times, was also investigated.

Synthesis and Crystal Structures of Benzimidazole-2-thione Derivatives by Alkylation Reactions.

Alkylated, benzylated and bromoalkylated benzimidazole-thione that intramolecularly heterocyclized to 3,4-dihydro-2H-[1,3]thiazino[3,2-a]benzimidazole were synthesized. The chemical structure of the synthesized product was characterized by Infra Red, ¹H-NMR, (13)C-NMR, and Mass spectroscopy. Furthermore, the molecular structures of 8 and 9 were confirmed by X-ray single crystallography in different space groups, Pbca and P21/c, respectively.

New Diethyl Ammonium Salt of Thiobarbituric Acid Derivative: Synthesis, Molecular Structure Investigations and Docking Studies.

The synthesis of the new diethyl ammonium salt of diethylammonium(E)-5-(1,5-bis(4-fluorophenyl)-3-oxopent-4-en-1-yl)-1,3-diethyl-4,6-dioxo-2-thioxohexaydropyrimidin-5-ide 3 via a regioselective Michael addition of N,N-diethylthiobarbituric acid 1 to dienone 2 is described. In 3, the carboanion of the thiobarbituric moiety is stabilized by the strong intramolecular electron delocalization with the adjacent carbonyl groups and so the reaction proceeds without any cyclization. The molecular structure investigations of 3 were determined by single-crystal X-ray diffraction as well as DFT computations. The theoretically calculated (DFT/B3LYP) geometry agrees well with the crystallographic data. The effect of fluorine replacement by chlorine atoms on the molecular structure aspects were investigated using DFT methods. Calculated electronic spectra showed a bathochromic shift of the π-π* transition when fluorine is replaced by chlorine. Charge decomposition analyses were performed to study possible interaction between the different fragments in the studied systems. Molecular docking simulations examining the inhibitory nature of the compound show an anti-diabetic activity with Pa (probability of activity) value of 0.229.

An Expedient Regio- and Diastereoselective Synthesis of Hybrid Frameworks with Embedded Spiro[9,10]dihydroanthracene [9,3']-pyrrolidine and Spiro[oxindole-3,2'-pyrrolidine] Motifs via an Ionic Liquid-Mediated Multicomponent Reaction.

A series of hitherto unreported anthracene-embedded dispirooxindoles has been synthesized via a one-pot three-component 1,3-dipolar cycloaddition reaction of an azomethine ylide, generated in situ from the reaction of isatin and sarcosine to 10-benzylideneanthracen-9(10H)-one as a dipolarophile in 1-butyl-3-methylimidazolium bromide([bmim]Br), an ionic liquid. This reaction proceeded regio- and diastereoselectively, in good to excellent yields.

Synthesis, Characterization, and Anti-Cancer Activity of Some New N'-(2-Oxoindolin-3-ylidene)-2-propylpentane hydrazide-hydrazones Derivatives.

Eight novel N'-(2-oxoindolin-3-ylidene)-2-propylpentane hydrazide-hydrazone derivatives 4a-h were synthesized and fully characterized by IR, NMR ((1)H-NMR and (13)C-NMR), elemental analysis, and X-ray crystallography. The cyto-toxicity and in vitro anti-cancer evaluation of the prepared compounds have been assessed against two different human tumour cell lines including human liver (HepG2) and leukaemia (Jurkat), as well as in normal cell lines derived from human embryonic kidney (HEK293) using MTT assay. The compounds 3e, 3f, 4a, 4c, and 4e revealed promising anti-cancer activities in tested human tumour cells lines (IC50 values between 3 and 7 µM) as compared to the known anti-cancer drug 5-Fluorouracil (IC50 32-50 µM). Among the tested compounds, 4a showed specificity against leukaemia (Jurkat) cells, with an IC50 value of 3.14 µM, but this compound was inactive in liver cancer and normal cell lines.

Synthesis, spectroscopic investigations (X-ray, NMR and TD-DFT), antimicrobial activity and molecular docking of 2,6-bis(hydroxy(phenyl)methyl)cyclohexanone.

The synthesis of 2,6-bis(hydroxy(phenyl)methyl)cyclohexanone 1 is described. The molecular structure of the title compound 1 was confirmed by NMR, FT-IR, MS, CHN microanalysis, and X-ray crystallography. The molecular structure was also investigated by a set of computational studies and found to be in good agreement with the experimental data obtained from the various spectrophotometric techniques. The antimicrobial activity and molecular docking of the synthesized compound was investigated.

Synthesis, molecular structure and spectroscopic investigations of novel fluorinated spiro heterocycles.

This paper describes an efficient and regioselective method for the synthesis of novel fluorinated spiro-heterocycles in excellent yield by cascade [5+1] double Michael addition reactions. The compounds 7,11-bis(4-fluorophenyl)-2,4-dimethyl- 2,4-diazaspiro[5.5] undecane-1,3,5,9-tetraone (3a) and 2,4-dimethyl-7,11-bis (4-(trifluoromethyl)phenyl)-2,4-diazaspiro[5.5]undecane-1,3,5,9-tetraone (3b) were characterized by single-crystal X-ray diffraction, FT-IR and NMR techniques. The optimized geometrical parameters, infrared vibrational frequencies and NMR chemical shifts of the studied compounds have also been calculated using the density functional theory (DFT) method, using Becke-3-Lee-Yang-Parr functional and the 6-311G(d,p) basis set. There is good agreement between the experimentally determined structural parameters, vibrational frequencies and NMR chemical shifts of the studied compounds and those predicted theoretically. The calculated natural atomic charges using NBO method showed higher polarity of 3a compared to 3b.The calculated electronic spectra are also discussed based on the TD-DFT calculations.

Synthesis and Crystallographic Insight into the Structural Aspects of Some Novel Adamantane-Based Ester Derivatives.

Adamantyl-based compounds are commercially important in the treatments for neurological conditions and type-2 diabetes, aside from their anti-viral abilities. Their values in drug design are chronicled as multi-dimensional. In the present study, a series of 2-(adamantan-1-yl)-2-oxoethyl benzoates, 2(a-q), and 2-(adamantan-1-yl)-2-oxoethyl 2-pyridinecarboxylate, 2r, were synthesized by reacting 1-adamantyl bromomethyl ketone with various carboxylic acids using potassium carbonate in dimethylformamide medium at room temperature. Three-dimensional structures studied using X-ray diffraction suggest that the adamantyl moiety can serve as an efficient building block to synthesize 2-oxopropyl benzoate derivatives with synclinal conformation with a looser-packed crystal packing system. Compounds 2a, 2b, 2f, 2g, 2i, 2j, 2m, 2n, 2o, 2q and 2r exhibit strong antioxidant activities in the hydrogen peroxide radical scavenging test. Furthermore, three compounds, 2p, 2q and 2r, show good anti-inflammatory activities in the evaluation of albumin denaturation.

Benzofuranyl Esters: Synthesis, Crystal Structure Determination, Antimicrobial and Antioxidant Activities.

A series of five new 2-(1-benzofuran-2-yl)-2-oxoethyl 4-(un/substituted)benzoates 4(a-e), with the general formula of C8H5O(C=O)CH2O(C=O)C6H4X, X = H, Cl, CH3, OCH3 or NO2, was synthesized in high purity and good yield under mild conditions. The synthesized products 4(a-e) were characterized by FTIR, ¹H-, (13)C- and ¹H-(13)C HMQC NMR spectroscopic analysis and their 3D structures were confirmed by single-crystal X-ray diffraction studies. These compounds were screened for their antimicrobial and antioxidant activities. The tested compounds showed antimicrobial ability in the order of 4b < 4a < 4c < 4d < 4e and the highest potency with minimum inhibition concentration (MIC) value of 125 µg/mL was observed for 4e. The results of antioxidant activities revealed the highest activity for compound 4e (32.62% ± 1.34%) in diphenyl-2-picrylhydrazyl (DPPH) radical scavenging, 4d (31.01% ± 4.35%) in ferric reducing antioxidant power (FRAP) assay and 4a (27.11% ± 1.06%) in metal chelating (MC) activity.

Nanomolar detection of hypochlorite by a rhodamine-based chiral hydrazide in absolute aqueous media: application in tap water analysis with live-cell imaging.

By employing the oxidation property of hypochlorite (OCl(-)), a novel rhodamine-based hydrazide of the chiral acid ((S)-(-)-2-pyrrolidone-5-carboxylic acid) (RHHP) was designed and synthesized for detection of OCl(-) absolutely in aqueous medium at nanomolar level. The structure of the chiral sensor was also proved by the X-ray crystallography. The bioactivity and the application of the probe for detection of OCl(-) in natural water system have been demonstrated. A plausible mechanism for oxidation of the sensor followed by hydrolysis is also proposed. The sensibility of the receptor toward OCl(-) was studied in absolute aqueous media, and the detection limit of hypochlorite-mediated oxidation to the receptor in nanomolar level makes this platform (RHHP) an ultrasensitive and unique system for OCl(-) oxidation.

Three types of cytotoxic natural caged-scaffolds: pure enantiomers or partial racemates.

Two rare new natural products, the neocaged-xanthone pruniflorone T (1) and the rearranged caged-xanthone pruniflorone U (3), and the known caged-xanthone cochinchinone C (2) were isolated from the roots of Cratoxylum formosum ssp. pruniflorum. The unique structures of 1-3 were determined by analysis of NMR and X-ray diffraction data. The X-ray data of 1-3 revealed that they all exist with both enantiomers in their crystal packing. Separation of 1-3 by chiral HPLC led to the isolation of three pairs of enantiomers, (-)-1/(+)-1, (-)-2/(+)-2, and (-)-3/(+)-3, and their absolute configurations were determined by analysis of single-crystal X-ray diffraction and ECD spectroscopic data. A 1:1 mixture of 1 and 3 showed potent in vitro cytotoxicity against an MCF-7 human breast cancer cell line with an IC50 value of 0.11 µg/mL.

First order temperature dependent phase transition in a monoclinic polymorph crystal of 1,6-hexanedioic Acid: an interpretation based on the landau theory approach.

Crystals of 1,6-hexanedioic acid (I) undergo a temperature-dependent reversible phase transition from monoclinic P21/c at a temperature higher than the critical temperature (Tc) 130 K to another monoclinic P21/c at temperature lower than Tc. The phase transition is of first order, involving a discontinuity and a tripling of the b-axis at Tc whereas the other unit cell parameters vary continuously. The transition is described by the phenomenological Landau theory. The crystal structure analyses for data collected at 297(2) K and 120.0(1) K show that there is half of a molecule of (I) in the asymmetric unit at 297(2) K whereas there are one and a half molecules of (I) in the asymmetric unit at 120.0(1) K. At both temperatures, 297(2) and 120.0(1) K, intermolecular O-H···O hydrogen bonds link the molecules of I into infinite 1D chains along [101] direction. However there are significantly more O-H···O hydrogen bonds presented in the 120.0(1) K polymorph, thereby indicating this phase transition is negotiated via hydrogen bonds. The relationship of the conformational changes and hydrogen bonding for these two polymorphs are explained in detail.

Synthesis, X-ray diffraction, thermogravimetric and DFT analyses of pyrimidine derivatives.

An eco-benign synthesis of pyrimidine derivatives 2a,b containing different functional groups with different electronic character starting from nitroalkenes 1a and 2b has been described. The structures for 1a and 2a,b have been characterized by single crystal X-ray diffraction analysis. The thermal data of the molecules pointed towards important structural aspects of their stability. The mechanism of their thermal decomposition is discussed. The thermodynamic parameters of the dissociation steps were evaluated and discussed. DFT calculations reveal that the compound 1a possesses a high calculated dipole moment value (8.28 D) which indicates its high reactivity towards its surrounding molecules.

A greener, efficient approach to Michael addition of barbituric acid to nitroalkene in aqueous diethylamine medium.

An efficient method for the synthesis of a variety of pyrimidine derivatives 3a-t by reaction of barbituric acids 1a,b as Michael donor with nitroalkenes 2a-k as Michael acceptor using an aqueous medium and diethylamine is described. This 1,4-addition strategy offers several advantages, such as using an economic and environmentally benign reaction media, high yields, versatility, and shorter reaction times. The synthesized compounds were identified by 1H-NMR, 13C-NMR, CHN, IR, and MS. The structure of compound 3a was further confirmed by single crystal X-ray structure determination.