Thiophene Analogues Research Articles

Substituted thiophene-anthranilamides as potent inhibitors of human factor Xa

A series of thiophene-containing non-amidine factor Xa inhibitors is described. Simple methyl-substituted thiophene analogs were relatively weak inhibitors. However, introduction of hydrophilic substituents at C-4 or C-5 of the thiophene afforded inhibitors with low nanomolar potency. Optimization of the thiophene substituent at C-4 afforded subnanomolar inhibitors with improved in vitro anticoagulant activity. Incorporating basic amine substituents on the thiophene increased hydrophilicity and improved anticoagulant activity. The pharmacokinetic profile of one inhibitor was evaluated in dogs, and the X-ray crystal structure of this compound bound to factor Xa provides insight into the observed SAR for binding to factor Xa.

A Thienopyridazinone-Based Melanin-Concentrating Hormone Receptor 1 Antagonist with Potent in Vivo Anorectic Properties

Melanin-concentrating hormone receptor antagonists containing thieno- and a benzopyridazinone cores were designed and tested as potential anorectic agents. These ligands showed high affinity for the receptor, potent functional activity in vitro, and good oral bioavailabilty in rats. The thiophene analogue exhibited low iv clearance, long half-life, and high brain penetration. In obese rats, the thienopyridazinone demonstrated a dose-dependent reduction in feeding and body weight with doses between 1 and 10 mg kg-1.

Novel Combretastatin Analogues Endowed with Antitumor Activity

We studied the anticancer activity of a series of new combretastatin derivatives with B-ring modifications. The structure-activity relationship (SAR) information confirmed the importance of cis-stereochemistry and of a phenolic moiety in B-ring. We selected the benzo[b]thiophene and benzofuran combretastatin analogues 11 (ST2151) and 13 (ST2179) and their phosphate prodrugs (29 and 30) for their high antitumor activity in in vitro and in vivo models. Cell exposure to IC50 of 11, 13, and CA-4 led to the arrest of various cell types in the G2/M phase of the cell cycle and induction of apoptosis. Mainly, 11 and 13 induced the formation of multinucleated cells with abnormal chromatin distribution, with only a minimal effect on the microtubule organization, with respect to CA-4. Interestingly, both the pharmacokinetic profile of 29 and its in vivo antitumor effect and those of 30, active even after oral administration, suggest additional pharmacological differences between these compounds and CA-4P.

Synthesis, photochemical synthesis, DNA binding and antitumor evaluation of novel cyano- and amidino-substituted derivatives of naphtho-furans, naphtho-thiophenes, thieno-benzofurans, benzo-dithiophenes and their acyclic precursors

As a part of the research on the improvement of an alternative to conventional photodynamic therapy by light-induced formation of intercalators, we synthesized a series of novel heterocyclic compounds and their acyclic precursors. We now report details about their synthesis/characterization in respect to their potential of photoinduced cyclization, interactions with DNA and inhibition of the tumor cell growth in vitro. Among studied compounds only amidino-furyl-substituted phenyl acrylates were efficiently converted to the corresponding naphthofuranes, while their thiophene analogues, all non-charged derivatives and amidino-phenyl-substituted analogues didn't show acceptable photoconversion. The significantly stronger antiproliferative activity of cyclic analogues could be correlated to the property of these molecules to intercalate into DNA. The acyclic molecules did not show any interaction with DNA, correlating with the inferior biological activity, except for one cyano-bearing molecule.

Fatigue Property of Oxidized Photochromic Dithienylethene Derivative for Permanent Optical Recording

Photochromic diarylethenes, such as 1,2-bis(2-methyl-1benzothiophene-3-yl)perfluorocyclopentene (BTF6) and 1,2-bis(2,5-dimethylthien-3-yl)perfluorocyclopentene (DMTF6), have been extensively investigated in recent years in order to develop materials for molecular photonic devices such as optical memory and switch. In the design of photochromic materials, thermal stability and fatigue resistant are important features to be considered. The thiophene analogues undergo photochromic ring closure efficiently but the fatigue property is generally low, resulting irreversible photochromism. If the photochromism is in an irreversible manner it could be applied in the permanent optical recording such as write once read many (WORM) memory. This motivates us to examine the effect of oxidation in the photophysical properties of diarylethenes with thiophene unit. As the thiophene analogues, we chose DMTF6 and its oxidized analogue, 1,2-bis(2,5-dimethylthien-1,1-dioxide-3-yl)perfluorocyclopentene (DMTFO4). Herein we report the synthesis and characterization of the photochromic properties including the fatigue property of DMTFO4. DMTF6 was prepared according to the procedures described in the literature. DMTFO4 was prepared from the oxidation of DMTF6 using 3-chloroperbenzoic acid (mCPBA) in 85% yield. The structure of DMTF6 and DMTFO4 was characterized using H-NMR and HRMS. Figure 1 shows the change of absorption spectra of DMTF6 (A) and DMTFO4 (B), as a function of time in ethyl acetate solution (1 × 10−5 M) at room temperature upon 312 nm irradiation using hand-held lamp. Upon UV illumination, the open-ring isomer of DMTF6 (o-DMTF6) and DMTFO4 (o-DMTFO4) undergoes photo-cyclization reaction showing new absorption bands at 480 nm and 360 nm for c-DMTF6 and c-DMTFO4, respectively. Upon visible illumination, the c-DMTF6 is completely returned back to the corresponding open-ring isomer (Figure 1C), whereas the absorption spectrum of c-DMTFO4 slightly changes and doesn’t match with corresponding o-DMTFO4 as can be seen in Figure 1D. This result implies that an irreversible side reaction might be occurred from c-DMTFO4 under UV irradiation. To elucidate the origin of the spectral changes in absorption spectra of DMTFO4 upon UV exposure, we examined H-NMR change under UV light irradiation for 20 hours. Figure 2 shows H-NMR of the thiophene ring protons of

Structural and electronic properties of substituted terthiophenes

Several 3′-(2-arene-l-yl-vinyl)-[2,2′;5′,2′′]terthiophenes and their thiophene analogues were synthesised by Wittig, Wadsworth-Emmons or Knovenagel condensations in good to moderate yields and their electronic absorption and emission spectra were investigated. The spectra are consistent with the presence of two independent chromophores in the ground state together with a single emission from the excited state. There would appear to be exceptions in the analogous cross-linked terthiophene derivatives. A charge transfer effect was also observed for the terthiophene with an indandione substituent.

New thiophene analogues of kenpaullone: synthesis and biological evaluation in breast cancer cells

Thieno analogues of kenpaullone have been synthesized using an established method. We investigated the effect of five structural analogues of kenpaullone on vincristine sensitive and resistant MCF7 (human mammary adenocarcinoma) cells. One analogue, 8-Bromo-6,11-dihydro-thieno-[3′,2′:2,3]azepino[4,5-b]indol-5(4H)-one ( 3a), showed an antiproliferative activity in the drug sensitive cell line that led to cell accumulation in G2/M phase. In addition, repression of cdk1, a G2/M transition key regulator, as well as induction of p21 were observed at the mRNA level. Programmed cell death (apoptosis) was induced in early time treatments and was accompanied by p53 mRNA induction. The antiproliferative and proapoptotic properties of 3a make this CDK inhibitor an interesting candidate for further investigations.

Enhanced electron injection and efficiency in blended-layer organic light emitting diodes with aluminium cathodes: new 2,5-diaryl-1,3,4-oxadiazole–fluorene hybrids incorporating pyridine units

This work focuses on the first 2,5-diaryl-1,3,4-oxadiazole–fluorene hybrids which incorporate pyridine units within the π-electron system, viz. 2,7-bis{5-[2-(4-dodecyloxyphenyl)-1,3,4-oxadiazol-5-yl]-2-pyridyl}-9,9-dihexylfluorene (6) and 2,7-bis{5-[2-(4-dodecyloxyphenyl)-1,3,4-oxadiazol-5-yl]-2-pyridyl}spirobifluorene (7). The thiophene analogue 2,7-bis{5-[5-(4-tert-butylphenyl)-1,3,4-oxadiazol-2-yl]-thien-2-yl}-9,9-dihexylfluorene 11 was also synthesised and its X-ray crystal structure was obtained. There is a progressive red shift in the UV–Vis absorption and photoluminescence spectra on replacing benzene (8) with pyridine (6) and thiophene (11) consistent with increased planarity of the π-system and reduced HOMO–LUMO gap along the series. Calculations at the DFT (density functional theory) level establish that inclusion of the pyridyl rings in 6 and 7 considerably enhances the electron affinity of the system, compared to phenyl analogues. Single-layer organic light-emitting diodes (OLEDs) have been fabricated by spin-coating blends of poly[2-(2-ethylhexyloxy)-5-methoxy-1,4-phenylenevinylene] (MEH–PPV) as the emissive material with added electron transport compounds 6 or 7 to enhance electron injection. The external quantum efficiencies of the devices were greatly enhanced compared to pure MEH–PPV reference devices. ITO/PEDOT ∶ PSS/MEH–PPV : 7 (30 ∶ 70% by weight)/Al devices exhibited an external quantum efficiency (EQE) of 0.5% and a luminous efficiency of 0.93 cd A−1 at 9.5 V and a luminance of 100 cd m−2. The modest increase in efficiency for the same device when Al was replaced by a Ca/Al cathode (EQE 0.6% and 1.2 cd A−1 at 10.5 V) suggests that the two methods of enhancing electron injection into the MEH–PPV emitter are mutually exclusive. Utilising blended layers is an attractive alternative to using Ca electrodes, which are highly reactive and are unstable in the atmosphere.

Desulfurization of Dibenzothiophene, Benzothiophene, and Other Thiophene Analogs by a Newly Isolated Bacterium, <I>Gordonia alkanivorans</I> Strain 1B

A novel bacterium, Gordonia alkanivorans strain 1B, was isolated from hydrocarbon-contaminated soil. Assessment of the biodegradation of distinct organic sulfur-compounds, such as dibenzothiophene (DBT), benzothiophene (BT), DBT sulfone, and alkylated tiophenic compounds, as the sole source of sulfur was investigated. G. alkanivorans strain 1B was able to remove selectively the sulfur from DBT while keeping intact the remaining carbon-carbon structure. Orthophenyl phenol (2-hydroxybiphenyl) was the only detected metabolic product. The bacterial desulfurization activity was repressed by sulfate. G. alkanivorans strain 1B consumed 310 microM DBT after 120 h of cultivation, corresponding to a specific desulfurization rate of 1.03 micromol/(g of dry cells x h). When an equimolar mixture of DBT/BT was used as a source of sulfur in the growth medium, G. alkanivorans strain 1B assimilated both compounds in a sequential manner, with BT as the preferred source of sulfur. Only when BT concentration was decreased to a very low level was DBT utilized as the source of sulfur for bacterial growth. The specific desulfurization overall rates of BT and DBT obtained were 0.954 and 0.813 micromol/(g of dry cells x h), respectively. The newly isolated G. alkanivorans strain 1B has good potential for application in the biodesulfurization of fossil fuels.

QSAR studies on some thiophene analogs as anti-inflammatory agents: enhancement of activity by electronic parameters and its utilization for chemical lead optimization

Small molecule heterocycle is an integral part of new drug discovery in anti-inflammatory research. In our previous papers we reported the synthesis of thiophene analogs substituted at the fifth position with α-oximino propionic ester moiety and the fact that such new chemical entities exhibit anti-inflammatory activity in male/female Sprague–Dawley rats. In this paper we report the quantitative structure activity relationship (QSAR) studies of a series of 43 thiophene analogs. The analogs when subjected to cluster analysis technique led to the formation of four homogeneous groups. The cluster analysis technique grouped the 2-anilino-5-substituted-4-methyl-thiophene-3-carboxylic acid methyl esters as one homogeneous group. The clusters were individually taken up for a Hansch type of QSAR study with 10 molecular descriptors. The QSAR equations generated were cross validated by the leave out one method. The studies gave an insight into the dominant role played by electronic properties like energy of the lowest unoccupied molecular orbital ( E LUMO) and dipole moment (dipole) in modulating the anti-inflammatory activity. From the QSAR studies a three point pharmacophore has been established for designing novel anti-inflammatory molecules.

5-Amidinobenzo[ b]thiophenes as dual inhibitors of factors IXa and Xa

Syntheses and SAR studies of 5-amidinobenzo[ b]thiophene analogs provided compounds with low submicromolar factor IXa activity and equal or slightly better selectivity relative to factor Xa.

Design, synthesis, and pharmacological evaluation of some 2-[4-morpholino]-3-aryl-5-substituted thiophenes as novel anti-inflammatory agents: generation of a novel anti-inflammatory pharmacophore

Compounds incorporating a thiophene moiety, a pi excess five membered heterocycle, have attracted a great deal of research interest owing to the therapeutic utility of the template as useful drug molecular scaffolding. Recently we reported the anti-inflammatory activity profile exhibited by two thiophene analogs, AP84 and AP82 in acute and chronic models of inflammation. The good activity profile exhibited by AP84, a 3-(substituted aryl)-2-(4-morpholino)-5-heteroaryl substituted analog of thiophene, in the formalin induced rat paw edema chronic model as compared to a weak activity in acute carrageenin induced rat paw edema, and the slightly better protection exhibited in the acute model by AP82 (27%), the 5-aroyl analog provided an impetus for a proper exploration of their structural types. In this paper we report the synthesis and pharmacological evaluation of some novel, 2-(4-morpholino)-3-(substituted aryl)-5-substituted thiophenes, as possible anti-inflammatory leads. The 3-(4-chlorophenyl)-2-(4-morpholino) thiophene analogs AP49, AP158, and AP88 provided a protection of 20%, 23%, and 20%, respectively, when screened for anti-inflammatory activity in carrageenin induced rat paw edema, an acute in vivo model, comparable to that of AP82, at a dose level of 100 mg/kg body weight p.o. compared to ibuprofen as standard. The replacement of the 3-(4-chlorophenyl) moiety with the 3-phenyl moiety gave rise to AP50 (30%), AP159 (38%), AP27 (0%), and AP92 (38%), with three analogs being more active in the acute model. Alteration of the group para to the phenyl ring at third position, from chloro, to methyl mercapto gave rise to the 3-(4-methylmercapto-phenyl) analogs AP54 (20%), AP160 (0%), and AP73 (52%), with only one analog appearing to be better than AP82. These results indicate that 4-methane sulfonyl aroyl group at 5-position and other substituents of different quadrants of Craig plot on the phenyl moiety at the third position could lead to more potent candidates. However, alteration of aroyl to substituted pyridyl at 5-position with a phenyl group at the third position as in AP26 gave rise to much better protection (66%) again reinforcing the importance of the heteroaryl ring at the fifth position and implying its utility in the composition of a novel pharmacophore for designing better trisubstituted thiophenes as anti-inflammatory agents.

Efficient Isomer‐Pure Synthesis of a Benzo[b]thiophene Analogue of Pentacene.

AbstractFor Abstract see ChemInform Abstract in Full Text.

2,6-Diphenylbenzo[1,2-b:4,5-b']dichalcogenophenes: a new class of high-performance semiconductors for organic field-effect transistors.

2,6-Diphenylbenzo[1,2-b:4,5-b']dichalcogenophenes including thiophene, selenophene, and tellurophene analogues as organic semiconductors for field-effect transistors were effectively synthesized in three steps from commercially available 1,4-dibromobenzene. All three benzodichalcogenophenes acted as good p-type semiconductors, and particularly the selenophene analogue, 2,6-diphenylbenzo[1,2-b:4,5-b']diselenophene, showed high FET mobility of 0.17 cm2 V-1 s-1.

Synthesis and COX-2 inhibitory properties of N-phenyl- and N-benzyl-substituted amides of 2-(4-methylsulfonylphenyl)cyclopent-1-ene-1-carboxylic acid and of their pyrazole, thiophene and isoxazole analogs

Some N-phenyl- ( 7a–10a) and N-benzyl-substituted ( 7b–10b) amido analogs of cyclooxygenase (COX-2) selective tricyclic non-steroidal anti-inflammatory drugs have been synthesized with the aim to obtain information on the structural requirements for the COX-inhibitory activity. Compounds 7–10 were tested in vitro for their inhibitory properties only towards COX-2 enzyme by measuring prostaglandin E2 (PGE2) production on activated J774.2 macrophages. Some of the new compounds ( 7a, 8a, 9a and 9b) showed a modest activity, with percentage inhibition values near 30% at a concentration of 10 μM. These data have been tentatively explained by a conformational study which indicates that at least the N-phenyl-substituted amides 7a–9a present steric hindrances which may prevent a good interaction with COX-2 active site.

Vapour deposited films of quinoidal biselenophene and bithiophene derivatives as active layers of n-channel organic field-effect transistors

n-Channel OFETs using oligoselenophene- and oligothiophene-based semiconductors as active layers have been successfully fabricated, and the field-effect mobilities for the selenophene-based compounds are found to be higher than those for the thiophene analogues.

Synthesis and pharmacological evaluation of (Z)-9-(heteroarylmethylene)-7-azatricyclo[4.3.1.0(3,7)]decanes: thiophene analogues as potent norepinephrine transporter inhibitors.

To further explore the structure-activity relationships (SARs) of certain tropanes, and to gain insights into the structural features required for high activity and selectivity at norepinephrine transporters (NET), we have introduced both five- and six-membered heteroaromatic moieties such as substituted pyridyl, pyrazinyl, pyrimidyl, thiazolyl, and mono- or disubstituted thienyl groups into conformationally constrained, tricyclic tropane analogues. A number of (Z)-9-(heteroarylmethylene)-7-azatricyclo[4.3.1.0(3,7)]decanes were synthesized, and their abilities to block dopamine, serotonin, and norepinephrine reuptake by their respective transporters were evaluated. It was found that the five- or six-membered N-containing aromatics are too basic to display high NET activity, while some of the thiophene analogues were identified as potent and selective NET inhibitors.

Application of Directed Metallation in Synthesis. Part 3. Studies in the Synthesis of (.+‐.)‐Semivioxanthin and Its Analogues.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Application of XPS in research on occurrence of organic sulfur in vitrain : Dai, S.-F. et al. Zhongguo Kuangye Daxue Xuebao, 2002, 31, (3), 225–229. (In Chinese)

Occurrence of organic sulfur in the hand picked vitrain samples from coal seams 9, 12 and 15 in Wuda coalfield, located on the western edge of Ordos Basin, was studied using the XPS technology. The research shows that the versatile occurrence of organic sulfur are determined by the pre coal material, sedimentary environment, and catagenesis. The lower organism, such as bacteria and alga into the swamp in large quantities during the peat accumulation might be the main reason for the thiophene analogue dominating (50.67%) in the organic sulfur in No.9 coal seam. The thiophene analogue content increases along with the coal rank ( R o,ran ranges from 0.96% for No.9 coal seam to 1.09% for No.15 coal seam). The high content of sulfone in No.15 coal seam is probably related to the relative high content of exinite ( w (exinite)=1.6%).

Stannous Chloride Mediated Reductive Cyclization—Rearrangement of Nitroarenyl Ketones.

AbstractFor Abstract see ChemInform Abstract in Full Text.