Thiophenyl Derivatives Research Articles

Thiophenyl Derivatives of Nicotinamide Are Metabolized by the NAD Salvage Pathway into Unnatural NAD Derivatives That Inhibit IMPDH and Are Toxic to Peripheral Nerve Cancers.

N-Pyridinylthiophene carboxamide (compound 21) displays activity against peripheral nerve sheath cancer cells and mouse xenografts by an unknown mechanism. Through medicinal chemistry, we identified a more active derivative, compound 9, and found that only analogues with structures similar to nicotinamide retained activity. Genetic screens using compound 9 found that both NAMPT and NMNAT1, enzymes in the NAD salvage pathway, are necessary for activity. Compound 9 is metabolized by NAMPT and NMNAT1 into an adenine dinucleotide (AD) derivative in a cell-free system, cultured cells, and mice, and inhibition of this metabolism blocked compound activity. AD analogues derived from compound 9 inhibit IMPDH in vitro and cause cell death by inhibiting IMPDH in cells. These findings nominate these compounds as preclinical candidates for the development of tumor-activated IMPDH inhibitors to treat neuronal cancers.

Design of donor-acceptor small molecules based on diazaisoindigo unit: Synthesis, theoretical calculations and photophysical studies

Two donor-acceptor-donor (D–A–D) and two donor-acceptor (D-A) small molecular systems involving alkyl bithiophene and thiophene derivatives as donor blocks and 5,5′- and 5-linked 7,7′-diazaisoindigo (DAIID) as acceptor blocks have been synthesized and investigated with theoretical calculations and photophysical studies. The incorporation of the thiophene groups led to significant changes in the UV–vis absorption spectra and electronic structure of the diazaisoindigo. Bithiophene and thiophene derivatives did not show fluorescence, in contrast to their dibrominated and brominated precursors. This fact was attributed to both a decrease of the radiative rate constant and an increase of the non-radiative deactivation associated to the incorporation of the thiophenyl groups. Additionally, picosecond transient absorption experiments revealed short time decays for the thiophenyl derivatives indicating a faster non-radiative deactivation associated to a rotation of the central double bond of 7,7′-diazaisoindigo in the excited state.

An Experimental and Theoretical Study of Dye Properties of Thiophenyl Derivatives of 2-Hydroxy-1,4-naphthoquinone (Lawsone).

A prospective study of the dye properties of non-toxic lawsone thiophenyl derivatives, obtained using a green synthetic methodology allowed for the description of their bathochromic shifts in comparison to those of lawsone, a well-known natural pigment used as a colorant that recently also has aroused interest in dye-sensitized solar cells (DSSCs). These compounds exhibited colors close to red, with absorption bands in visible and UV wavelength range. The colorimetric study showed that these compounds exhibited a darker color than that of lawsone within a range of colors depending on the substituent in the phenyl ring. Computational calculations employing Density Functional Theory (DFT) and Time-Dependent Density Functional Theory (TD-DFT), showed that the derivatives have lower excitation energies than lawsone, while the alignment of their frontier orbitals regarding the conduction bands of TiO2 and ZnO and the redox potential of the electrolyte I−/I3− suggests that they could be employed as sensitizers. The study of the interactions of the lawsone and a derivative with a TiO2 surface model by different anchoring modes, showed that the adsorption is thermodynamically favored. Natural bond orbital (NBO) analysis indicates a two-center bonding (BD) O-Ti as the main interaction of the dyes with TiO2.

Synthesis of 1,5-Anhydro-d-glycero-d-gluco-heptitol Derivatives as Potential Inhibitors of Bacterial Heptose Biosynthetic Pathways

A series of 1,5-anhydro-d-glycero-d-gluco-heptitol derivatives have been prepared from 3-O-benzyl-1,2-O-isopropylidene-d-glycero-d-gluco-heptofuranose via conversion into anomeric bromide and thiophenyl derivatives, followed by glycal formation and reductive desulfurization, respectively. Global deprotection of the protected intermediates afforded the 1,5-anhydro derivatives of the d-glycero-d-gluco- and 1,2-dideoxy-d-altro- configuration as well as the 1,5-anhydro-2-deoxy-d-altro-hept-1-enitol. In addition, the 7-O-phosphorylated d-glycero-d-gluco-heptose and its 1,5-anhydro analogue were prepared in good yields utilizing phosphoramidite chemistry. A novel heptitol analogue based on a 1-deoxynojirimycin scaffold was also elaborated via a Wittig­-type chain elongation followed by dihydroxylation, separation of the resulting epimers, and global deprotection. The target compounds, however, were not active as inhibitors of the bacterial sedoheptulose-7-phosphate isomerase GmhA.

Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity.

A series of N(6)-bicyclic and N(6)-(2-hydroxy)cyclopentyl derivatives of adenosine were synthesized as novel A1R agonists and their A1R/A2R selectivity assessed using a simple yeast screening platform. We observed that the most selective, high potency ligands were achieved through N(6)-adamantyl substitution in combination with 5'-N-ethylcarboxamido or 5'-hydroxymethyl groups. In addition, we determined that 5'-(2-fluoro)thiophenyl derivatives all failed to generate a signaling response despite showing an interaction with the A1R. Some selected compounds were also tested on A1R and A3R in mammalian cells revealing that four of them are entirely A1R-selective agonists. By using in silico homology modeling and ligand docking, we provide insight into their mechanisms of recognition and activation of the A1R. We believe that given the broad tissue distribution, but contrasting signaling profiles, of adenosine receptor subtypes, these compounds might have therapeutic potential.

Infra-red spectroscopic characteristics of naphthalocyanine in bis(naphthalocyaninato) rare earth complexes peripherally substituted with thiophenyl derivatives

The infra-red (IR) spectroscopic data for a series of eleven rare earth double-deckers MIII[Nc(SPh)8]2 (M=Y, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho and Er) have been collected and systematically investigated. For MIII[Nc(SPh)8]2, typical IR marker bands for the naphthalocyanine anion radical [Nc(SPh)8]− were observed at 1317–1325cm−1 as the most intense absorption bands, which can be attributed to the pyrrole stretching. As for Ce[Nc(SPh)8]2, the typical IR marker band was also observed at 1317cm−1, which shows that the cerium complex exists as the form of CeIII[Nc(SPh)8]2−[Nc(SPh)8]−. In addition, both the Q-bands of electronic absorption spectra and the typical IR absorption bands of naphthalocyanine radical anion [Nc(SPh)8]− move to the high energy as the decrease of rare earth metal ionic radius. These facts suggest that the π–π electron interaction in these double-deckers becomes stronger along with the lanthanide contraction.

Molecular Modeling Studies of Thiophenyl C-Aryl Glucoside SGLT2 Inhibitors as Potential Antidiabetic Agents.

A QSAR study on thiophenyl derivatives as SGLT2 inhibitors as potential antidiabetic agents was performed with thirty-three compounds. Comparison of the obtained results indicated the superiority of the genetic algorithm over the simulated annealing and stepwise forward-backward variable method for feature selection. The best 2D QSAR model showed satisfactory statistical parameters for the data set (r 2 = 0.8499, q 2 = 0.8267, and pred_r 2 = 0.7729) with four descriptors describing the nature of substituent groups and the environment of the substitution site. Evaluation of the model implied that electron-rich substitution position improves the inhibitory activity. The good predictive 3D-QSAR models by k-nearest neighbor (kNN) method for molecular field analysis (MFA) have cross-validated coefficient q 2 value of 0.7663 and predicted r 2 value of 0.7386. The results have showed that thiophenyl groups are necessary for activity and halogen, bulky, and less bulky groups in thiophenyl nucleus enhanced the biological activity. These studies are promising for the development of novel SGLT2 inhibitor, which may have potent antidiabetic activity.

Stabilizing Gold Adatoms by Thiophenyl Derivatives: A Possible Route toward Metal Redispersion

Tris(phenylthio)benzene molecules have been synthesized in order to explore their ability to trap single Au adatoms on an Au(111) surface. The resulting metal-organic complexes have been characterized with low-temperature scanning tunneling microscopy and infrared reflection absorption spectroscopy; possible structure models have been derived from density functional calculations. Upon room temperature deposition, the thiophenyl derivatives form dimer structures, comprising two molecules and six Au adatoms. Below 100 K, isolated molecules are found as well that have trapped up to six Au atoms. On the basis of the experimental results and calculated formation energies of the complexes, we discuss potential applications of the thioethers for the redispersion of metals on a catalyst surface. First experiments performed on Au particle ensembles prepared on alumina thin films suggest that the molecular ligands are indeed able to change the distribution of gold on the oxide surface.

Synthesis and evaluation of thiophenyl derivatives as inhibitors of alkaline phosphatase

Pathological calcifications induced by deposition of basic phosphate crystals or hydroxyapatite (HA) on soft tissues are a large family of diseases comprising of ankylosing spondylitis (AS), end-stage osteoarthritis (OA) and vascular calcification. High activity of tissue non-specific alkaline phosphatase (TNAP) is a hallmark of pathological calcifications induced by HA deposition. The use of TNAP inhibitor is a possible therapeutic option to address calcific diseases produced by HA deposition on soft tissues. We report the synthesis of a series of thiopheno-imidazo[2,1-b]thiazole derivatives which were evaluated as potential inhibitors of TNAP displaying a large range of IC(50) at pH 10.4 (from 42±13 μM to more than 800 μM).

Synthesis and biological evaluation of substituted thiophenyl derivatives of indane-1,3-dione

Indane-1, 3-dione ( 1) synthesized by condensation of diethyl phthalate and ethyl acetate in presence of sodium ethoxide gave sodium salt of ester derivative, which on neutralization in presence of sulphuric acid afford 1. Various thiols where converted to their respective disulphide ( 3) which on treatment with 1 gave 2-substituted thio phenyl derivatives ( 4a -g) of 1. The synthesized compounds were characterized on the basis of I.R and H 1 NMR. Synthesized compounds ( 4a-g) were investigated for their anticoagulant, analgesic, anti-inflammatory, antifungal, antibacterial and anticancer activities. Some of the synthesized compounds have shown moderate activities.

Synthesis and Biological Evaluation of Substituted Thiophenyl Derivatives of Indane‐1, 3‐Dione

Indane‐1, 3‐dione (1) synthesized by condensation of diethyl phthalate and ethyl acetate in presence of sodium ethoxide gave sodium salt of ester derivative, which on neutralization in presence of sulphuric acid afford 1. Various thiols where converted to their respective disulphide (3) which on treatment with 1 gave 2‐substituted thio phenyl derivatives (4a-g) of 1. The synthesized compounds were characterized on the basis of I.R and H1NMR. Synthesized compounds (4a-g) were investigated for their anticoagulant, analgesic, anti‐inflammatory, antifungal, antibacterial and anticancer activities. Some of the synthesized compounds have shown moderate activities.

Excited States and Two-Photon Absorption of Some Novel Thiophenyl Pt(II)−Ethynyl Derivatives

The photophysical characterization of two new compounds related to bis((4-(phenylethynyl)phenyl)ethynyl)bis(tributylphosphine)platinum(II), here abbreviated Pt1, is reported. For the first new compound ATP1, the inner phenyl rings (closer to the Pt atom) in Pt1 are replaced by thiophene rings bridging at the 2,5-positions. In compound ATP2, the outer phenyl groups are replaced by thiophene rings bonded at the 2-position. Specifically, we report on the fluorescence quantum yield, two-photon absorption, triplet decay times and two-photon absorption induced emission spectra of the molecules in THF solutions. The results were compared with those of Pt1 and Pt1 capped with an acetonide-protected 2,2-bis(methylol)propionic acid (bis-MPA) ester group (Pt1-G1). The photophysical properties of the organic dye 7-(diethylamino)coumarin (Coumarin 110) were determined and used as a reference material. The two-photon absorption cross section around 720-740 nm of ATP1 and ATP2 was found to be of the same order of magnitude as for Pt1-G1, i.e., between 5 and 10 GM, but slightly larger for ATP1 than for ATP2 (1 GM = 1 Göppert-Mayer = 10(-50) (cm(4) s)/photon). The fluorescence decay time of all compounds was found to be very short (subnanosecond) with quantum yields 0.0045, 0.0007, 0.0011 and 0.0020 for ATP1, ATP2, Pt1-G1 and Pt1, respectively, measured at excitation wavelength 373 nm. Just as Pt1 and Pt1-G1, both thiophenyl derivatives showed large intersystem crossing capabilities and phosphorescence, characteristic for a triplet state that can enhance the nonlinear absorption and optical power limiting by triplet state absorption. The phosphorescence emission of the thiophenyl derivatives was red-shifted in comparison with Pt1 and Pt1-G1, and the phosphorescence decay times were on the order of 200-500 ns, as for the Pt1 compound.

Isophthalato-Based 2D Coordination Polymers of Eu(III), Gd(III), and Tb(III): Enhancement of the Terbium-Centered Luminescence through Thiophene Derivatization

We present here the first examples of lanthanide ion complexes with only isophthalic acid or thiophenylisophthalic acid ligands. The complexes of isophthalic acid with Eu(3+) (1) and Tb(3+) (2) and the moderately soluble complexes of 5-thiophen-3-ylisophthalate with Eu(3+) (3), Gd(3+) (4), and Tb(3+) (5) were isolated as single crystals through gel crystallization. X-ray diffraction studies confirm the cross-linking structure of these complexes, which, in case of the thiophenyl derivatives, results in low solubility in common solvents. The two-dimensional isophthalato complex of Eu(3+) (1) crystallizes in the C2/c space group, with a = 22.154(4), b = 12.649(3), and c = 15.921(3) A, beta = 112.34(3) degrees, and V = 4126.7(14) A(3), while the one-dimensional Tb(3+) complex of the same ligand, 2, crystallizes in the space group P2(1)/c with a = 11.921(2), b = 10.838(2), and c = 17.499(4) A, beta = 92.44(3) degrees, and V = 2258.9(8) A(3). The thiophenylisophthalato complexes of Eu(3+) (3) and Gd(3+) (4) are two-dimensional and crystallize in the P2/n space group with parameters for 3 of a = 14.139(3), b = 10.684(2), and c = 15.138(3) A, beta = 102.51(3) degrees, and V = 2232.3(8) A(3) and parameters for 4 of a = 14.1195(13), b = 10.6594(10), and c = 15.1149(14) A, beta = 102.529(2) degrees, and V = 2220.7(4) A(3), while the Tb(3+) complex, 5, also two-dimensional, crystallizes in the P space group with a = 11.051(2), b = 14.528(3), and c = 15.041(3) A, alpha = 77.63(3), beta = 87.86(3), and gamma = 83.51(3) degrees, and V = 2343.48 A(3). All complexes of Eu(3+) and Tb(3+) luminesce in aqueous solution, and the luminescence lifetimes and quantum yields are 123.8 +/- 7.4, 0.14% (1), 475.1 +/- 14.5, 3.58% (3), 129.3 +/- 3.5, 0.19% (4), and 213.9 +/- 2.2 micros, 7.46% (5).

Synthetic studies on glycosphingolipids from protostomia phyla: synthesis of neogala-series glycolipid analogues containing a mannose residue from the earthworm Pheretima hilgendorfi.

Two kinds of glycosphingolipid analogues from the earthworm Pheretima hilgendorfi were synthesized as follows: the trisaccharide 2-(tetradecyl)hexadecyl alpha-D-mannopyranosyl-(1-->4)-beta-D-galactopyranosyl-(1-->6)-beta-D- galactopyranoside (13) and the tetrasaccharide 2-(tetradecyl) hexadecyl alpha-D-galactopyranosyl-(1-->6)-[alpha-D-mannopyranosyl-(1-->4)]-beta-D - galactopyranosyl-(1-->6)-beta-D-galactopyranoside (20) were synthesized by stepwise condensation of suitably protected monosaccharide units. A 2-(trimethylsilyl)ethyl 2,3,4-tri-O-benzoyl-beta-D-galactopyranoside derivative (5) was used as the glycosyl acceptor and thiophenyl derivatives of D-galactose and D-mannose were used as donors respectively.

Substrate Specificity of the H+-Sucrose Symporter on the Plasma Membrane of Sugar Beets (Beta vulgaris L.)

Previous results (TJ Buckhout, Planta [1989] 178: 393-399) indicated that the structural specificity of the H(+)-sucrose symporter on the plasma membrane from sugar beet leaves (Beta vulgaris L.) was specific for the sucrose molecule. To better understand the structural features of the sucrose molecule involved in its recognition by the symport carrier, the inhibitory activity of a variety of phenylhexopyranosides on sucrose uptake was tested. Three competitive inhibitors of sucrose uptake were found, phenyl-alpha-d-glucopyranoside, phenyl-alpha-d-thioglucopyranoside, and phenyl-alpha-d-4-deoxythioglucopyranoside (PDTGP; K(i) = 67, 180, and 327 micromolar, respectively). The K(m) for sucrose uptake was approximately 500 micromolar. Like sucrose, phenyl-alpha-d-thioglucopyranoside and to a lesser extent, PDTGP induced alkalization of the external medium, which indicated that these derivatives bound to and were transported by the sucrose symporter. Phenyl-alpha-d-3-deoxy-3-fluorothioglucopyranoside, phenyl-alpha-d-4-deoxy-4-fluorothioglucopyranoside, and phenyl-alpha-d-thioallopyranoside only weakly but competively inhibited sucrose uptake with K(i) values ranging from 600 to 800 micromolar, and phenyl-alpha-d-thiomannopyranoside, phenyl-beta-d-glucopyranoside, and phenylethyl-beta-d-thiogalactopyranoside did not inhibit sucrose uptake. Thus, the hydroxyl groups of the fructose portion of sucrose were not involved in a specific interaction with the carrier protein because phenyl and thiophenyl derivatives of glucose inhibited sucrose uptake and, in the case of phenyl-alpha-d-thioglucopyranoside and PDTGP, were transported.

ChemInform Abstract: β‐Angelica Lactone Epoxide: Chemical Behaviour and Some Synthetic Applications.

AbstractThe epoxide (II), derived from β‐angelica lactone (I), is converted to the hydroxylactones (V), (VI), (IX), and (X) and to the thiophenyl derivatives (VII) and (VIII) as shown in the reaction scheme.

Polyacetylenes in Hawaiian bidens

Leaves and roots of 19 species and six subspecies of Hawaiian Bidens were examined for polyacetylenes. Eleven C 13 hydrocarbons, aromatic and thiophenyl derivatives, one C 14 tetrahydropyran and three C 17 hydrocarbons were isolated all identified. All can be derived from a common precursor, oleic acid. Polyacetylenes were not detected in the leaves of 13 taxa although they are found in the roots of all. The occurrence of 2-[2-phenyl-ethyne-1-yl]-5 acetoxymethyl thiopene in Bidens has not been previously reported. Its ubiquitous presence is consistent with other evidence that the Hawaiian species are all derived from a single ancestral immigrant to the islands. Most taxa could be distinguished by their complement of polyacetylenes in roots and leaves. No variation was found to occur within taxa except in B. torta, in which each population had a unique array of polyacetylenes. Above the species level there appeared to be no taxonomically significant pattern to the distribution of polyacetylenes in this group.