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PubMed2005

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 alpha-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 (ELUMO) 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.

Animals↗
PubMed2005

Evaluation of the antioxidant properties of diarylamines in the benzo[b]thiophene series by free radical scavenging activity and reducing power.

The antioxidant properties of substituted diarylamines in the benzo[b]thiophene series were evaluated by their reducing power and free radical scavenging activity. The results were compared with those of standards: acid ascorbic for the first method and BHA and BHT for the second. For both methods it was possible to establish some structure-activity relationships (SARs) based on the position of the arylamination on the benzo[b]thiophene moiety, the presence of different substituents on the phenyl ring (F, 1 or 2 OMe) and on the thiophene ring (H, CO(2)Et, CO(2)H).

Amines↗
PubMed2000

Catalytic hydroprocessing of chlorobenzene: the effect of thiophene.

The catalytic hydrotreatment of chlorobenzene-thiophene mixtures has been studied using a Ni-Mo/gamma-Al(2)O(3) sulphided catalyst. Experimental runs were carried out in a batch reactor at constant temperature (T=300-320-340 degrees C) and hydrogen pressure (P=40 bar). The reaction medium was hexadecane. The experimental results show that chlorobenzene hydrodechlorination and thiophene hydrodesulphurization are not inhibited when chlorobenzene and thiophene are hydrotreated in admixture. The results that were obtained are of importance for the development of the hydrodechlorination (HDCl) process of chlorinated liquid wastes contaminated by other organic compounds.

Catalysis↗
PubMed1998

Synthesis and cytotoxicity of acetyl-4H,9H-naphtho[2,3-b]thiophene-4,9-diones.

Several new acetyl-4H,9H-naphtho[2,3-b]thiophene-4,9-diones were synthesized and evaluated for in vitro cytotoxicity by NCI against seven cancer cell types. 2,7-Diacetyl naphtho[2,3-b]thiophene-4,9-dione (9) showed significant cytotoxicity against leukemia cells with log GI50 values of -7.61 against SR cells and -7.18 against MOLT-4 cells. 3-Acetyl-naphtho[2,3-b]thiophene-4,9-dione (6) also demonstrated potent cytotoxicity in the latter cell line with log GI50 < -8.

Antineoplastic Agents↗
PubMed2003

Shape selective recognition of T.A base pairs by hairpin polyamides containing N-terminal 3-methoxy (and 3-chloro) thiophene residues.

Hairpin polyamides selectively recognize predetermined DNA sequences with affinities comparable to naturally occurring proteins. Internal side-by-side pairs of unsymmetrical aromatic rings within the minor groove of DNA distinguish each of the four Watson-Crick base pairs. In contrast, N-terminal ring pairs exhibit less specificity, with the exception of Im/Py targeting G.C base pairs. In an effort to explore the sequence specificity of new ring pairs, a series of hairpin polyamides containing 3-substituted-thiophene-2-carboxamide residues at the N-terminus was synthesized. An N-terminal 3-methoxy (or 3-chloro) thiophene residue paired opposite Py displayed 6- (and 3-) fold selectivity for T.A relative to A.T base pair, while disfavoring G,C base pairs by >200-fold. Our data suggests shape selective recognition with projection of the 3-thiophene substituent (methoxy or chloro) to the floor of the minor groove.

Adenine↗
PubMed2004

Thiophene-based diamidine forms a "super" at binding minor groove agent.

The DNA minor groove is the interaction site for many enzymes and transcription control proteins and as a result, development of compounds that target the minor groove is an active research area. In an effort to develop biologically active minor groove agents, we are preparing and exploring the DNA interactions of a systematic set of diamidine derivatives with a powerful array of methods including DNase I footprinting, biosensor-SPR methods, and X-ray crystallography. Surprisingly, conversion of the parent phenyl-furan-phenyl diamidine to a phenyl-thiophene-benzimidazole derivative yields a compound with over 10-fold-increased affinity for the minor groove at AT sequences. Single conversion of the furan to a thiophene or a phenyl to benzimidazole does not cause a similar increase in affinity. X-ray results indicate a small bond angle difference between the C-S-C angle of thiophene and the C-O-C angle of furan that, when amplified out to the terminal amidines of the benzimidazole compounds, yields a very significant difference in the positions of the amidines and their DNA interaction strength.

Adenine↗
PubMed2005

A 2D solid-state NMR experiment to resolve overlapping aromatic resonances of thiophene-based nematogens.

In this study, we demonstrate the feasibility of resolving overlapping 13C chemical shift spectral lines of aromatic rings in a thiophene-based nematogen in the mesophase using a 2D PITANSEMA solid-state NMR method. This technique provided the information about chemical shift values as well as dipolar couplings that are used for determining the orientational order parameter. Large C-H dipolar coupling values measured for thiophene in contrast to phenyl rings suggest that the heterocyclic ring is not part of the molecular axis. Using the order parameter, we determined the orientation of C-H vectors of the thiophene ring. We believe that the 2D solid-state NMR can be extended to other types of liquid crystalline materials such as the banana-based mesogens for determining the orientational order and bent angle.

Benzoates↗
PubMed2006

Antifungal activity of thiophenes from Echinops ritro.

Extracts from 30 plants of the Greek flora were evaluated for their antifungal activity using direct bioautography assays with three Colletotrichum species. Among the bioactive extracts, the dichloromethane extract of the radix of Echinops ritro (Asteraceae) was the most potent. Bioassay-guided fractionation of this extract led to the isolation of eight thiophenes. Antifungal activities of isolated compounds together with a previously isolated thiophene from Echinops transiliensis were first evaluated by bioautography and subsequently evaluated in greater detail using a broth microdilution assay against plant pathogens Colletotrichum acutatum, Colletotrichum fragariae, Colletotrichum gloeosporioides, Botrytis cinerea, Fusarium oxysporum, Phomopsis viticola, and Phomopsis obscurans. 5'-(3-Buten-1-ynyl)-2,2'-bithiophen (1), alpha-terthienyl (2), and 2-[pent-1,3-diynyl]-5-[4-hydroxybut-1-ynyl]thiophene (5) at 3 and 30 microM were active against all three Colletotrichum species, F. oxysporum, P. viticola, and P. obscurans.

Ascomycota↗
PubMedDate not supplied

Synthesis and mutagenicity of trans-dihydrodiol metabolites of benzo[b]naphtho[2,1-d]thiophene.

The syntheses of potentially important metabolites of benzo[b]naphtho[2,1-d]thiophene ([2,1]BNT)--trans-1,2-dihydroxy-1,2-dihydrobenzo[b]naphtho[2,1- d]thiophene ([2,1]BNT-1,2-diol) and trans-3,4-dihydroxy-3,4-dihydrobenzo[b]naphtho[2,1-d]thiophene ([2,1]BNT-3,4-diol)--are described. The syntheses involved preparation of the appropriate 1-(3-benzo[b]-thiopheneyl)-2-(methoxyphenyl)ethylenes followed by photocyclization to methoxy-[2,1]BNTs, hydrolysis to hydroxy-[2,1]BNTs, oxidation to [2,1]BNT-diones, and NaBH4 reduction. The dihydrodiols were tested for mutagenicity in Salmonella typhimurium TA 100 with activation; [2,1]BNT-3,4-diol, which can form a bay region diol epoxide, was as mutagenic as [2,1]BNT whereas [2,1]BNT-1,2-diol was inactive. These results suggest that the metabolic activation of [2,1]BNT proceeds partially via formation of a bay region diol epoxide.

Carcinogenicity Tests↗
PubMed2000

Convulsive effects of thiophene, a heterocyclic hydrocarbon: behavioral, electrographic and c-Fos immunocytochemical studies.

The behavioral, electrographic and histopathological changes induced by the heterocyclic hydrocarbon thiophene were investigated in rats following intramuscular injection of 0.3 mL thiophene for 5 days. Generalized convulsions were noted in 29 out of 34 animals (85%) between 1 and 28 h after the final dose. Electroencephalography revealed that the discharges in the hippocampus and forebrain occurred simultaneously, although epileptic activity emerged more strongly from the hippocampus than from any other region. Neuron damage was detected histologically in the temporal and parietal neocortex, piriform gyrus, amygdaloid nucleus and cerebellar cortex, but not in the hippocampus. In contrast, c-Fos was induced widely in the cerebral cortex and hippocampus, and was most marked in the dentate gyrus. These findings suggest that the hippocampus plays a crucial role in seizure onset following thiophene injection.

Animals↗
PubMed2003

Two biologically active thiophene-3-carboxamide derivatives.

The two title compounds, 2-([(1Z)-[4-(dimethylamino)phenyl]methylene]amino)-4,5-dimethyl-N-(2-methylphenyl)thiophene-3-carboxamide, C(23)H(25)N(3)OS, (I), and 2-([(1E)-[4-(dimethylamino)phenyl]methylene]amino)-N-(4-methylphenyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide,C(25)H(27)N(3)OS, (II), show antibacterial and antifungal activities. The asymmetric unit of (II) contains two crystallographically independent molecules. The o-toluidine ring in (I) lies gauche with respect to the thiophene ring. In (II), the p-toluidine ring is coplanar with the thiophene ring in one molecule, but is tilted from it in the other molecule. Neither structure exhibits any significant intermolecular interactions, but in both, an intramolecular N-H.N hydrogen bond forms a pseudo-six-membered ring, thus locking the molecular conformation and removing conformational flexibility.

Aniline Compounds↗
PubMed2000

The crystal structures of human alpha-thrombin complexed with active site-directed diamino benzo[b]thiophene derivatives: a binding mode for a structurally novel class of inhibitors.

The crystal structures of four active site-directed thrombin inhibitors, 1-4, in a complex with human alpha-thrombin have been determined and refined at up to 2.0 A resolution using X-ray crystallography. These compounds belong to a structurally novel family of inhibitors based on a 2,3-disubstituted benzo[b]thiophene structure. Compared to traditional active-site directed inhibitors, the X-ray crystal structures of these complexes reveal a novel binding mode. Unexpectedly, the lipophilic benzo[b]thiophene nucleus of the inhibitor appears to bind in the S1 specificity pocket. At the same time, the basic amine of the C-3 side chain of the inhibitor interacts with the mostly hydrophobic proximal, S2, and distal, S3, binding sites. The second, basic amine side chain at C-2 was found to point away from the active site, occupying a location between the S1 and S1' sites. Together, the aromatic rings of the C-2 and C-3 side chains sandwich the indole ring of Trp60D contained in the thrombin S2 insertion loop defined by the sequence "Tyr-Pro-Pro-Trp." [The thrombin residue numbering used in this study is equivalent to that reported for chymotrypsinogen (Hartley BS, Shotton DM, 1971, The enzymes, vol. 3. New York: Academic Press. pp 323-373).] In contrast to the binding mode of more classical thrombin inhibitors (D-Phe-Pro-Arg-H, NAPAP, Argatroban), this novel class of benzo[b]thiophene derivatives does not engage in hydrogen bond formation with Gly216 of the thrombin active site. A detailed analysis of the three-dimensional structures not only provides a clearer understanding of the interaction of these agents with thrombin, but forms a foundation for rational structure-based drug design. The use of the data from this study has led to the design of derivatives that are up to 2,900-fold more potent than the screening hit 1.

Binding Sites↗
PubMed1992

Structure-activity studies of photoactivated antiviral and cytotoxic tricyclic thiophenes.

The photoactivated antiviral and cytotoxic activities of the naturally occurring thiophene, alpha-terthienyl (1), and 15 synthetic analogues were evaluated against murine cytomegalovirus and Sindbis virus, and murine mastocytoma cells. After irradiation with near UV light, alpha-terthienyl and most of its analogues had significant toxicity, with minimum inhibitory concentrations in the range of 0.02-40 microM. In the absence of near UV irradiation, only one analogue had antiviral activity and five were cytotoxic. The most active analogues were those containing carboxylic acid, hydroxyl, or cyano substituents. Quantitative structure-activity relationship analysis of thiophene phototoxicity suggested that the rate of singlet oxygen production is the primary determinant of antiviral and cytotoxic activities. For phototoxicity against murine cytomegalovirus, a significant role for hydrophobicity was also demonstrated. Tricyclic thiophenes show significant potential for photochemotherapy of viral infections and cancer, and further evaluation in animal models is recommended.

3T3 Cells↗
PubMed1991

Evaluation of in-vitro leishmanicidal activity of hydrazones of thiophene carboxaldehydes against promastigotes of Leishmania infantum and Leishmania tropica.

The lack of leishmanicidal drugs has prompted the synthesis and testing of new hydrazones of thiophene carboxaldehydes against three Leishmania strains. The compounds were obtained by condensation of appropriate hydrazines with thiophene 2-carboxaldehyde (series 1), thiophene 3-carboxaldehyde (series 2), and 5-nitrothiophene-2-carboxaldehyde (series 3). Leishmanicidal activity was assessed against promastigotes of Leishmania strains, grown in-vitro in nutrient broth medium complemented with fresh rabbit blood. The minimal inhibitory concentrations were evaluated against pentamidine, as a reference drug. Several compounds exhibited significant leishmanicidal activity, the best being ten times more active than pentamidine.

Animals↗
PubMed1998

A review of the occurrence, toxicity, and biodegradation of condensed thiophenes found in petroleum.

Condensed thiophenes comprise a significant portion of the organosulfur compounds in petroleum and in other products from fossil fuels. Dibenzothiophene (DBT) has served as a model compound in biodegradation studies for over two decades. However, until quite recently, few other organosulfur compounds were studied, and their fates in petroleum-contaminated environments are largely unknown. This paper presents a review of the types of organosulfur compounds found in petroleum and summarizes the scant literature on toxicity studies with condensed thiophenes. Reports on the biodegradation of benzothiophene, alkylbenzothiophenes, DBT, alkylDBTs, and naphthothiophenes are reviewed with a focus on the identification of metabolites detected in laboratory cultures. In addition, recent reports on quantitative studies with DBT and naphtho[2,1-b]thiophene indicate the existence of polar sulfur-containing metabolites that have escaped detection and identification.

Biodegradation, Environmental↗
PubMed1999

Synthesis and in vitro antiprotozoal activity of thiophene ring-containing quinones.

A series of quinones (3a-i, 4-9, 11) and aromatic compounds (2a, 2d, 2g) containing the thiophene ring were tested in vitro against the trypomastigote form of Trypanosoma cruzi and the promastigote forms of Leishmania. The quinones 3a-i, 4, 5a, b, 6 and 9 having the thiophene ring fused to a quinone nucleus were the most active members of the series. The electron affinities of the benzo[b]thiophene-4,7-quinones 3, evaluated by their LUMO energies and halfwave potentials, are reported.

Animals↗
PubMed2004

New 3-[4-(2,3-dihydro-14-benzodioxin-5-yl)piperazin-1-yl]-1-(5-substituted benzo[b]thiophen-3-yl)propanol derivatives with dual action at 5-HT(1A) serotonin receptors and serotonin transporter as a new class of antidepressants.

Compounds derived from 2,3-dihydro-(1,4-benzodioxin-5-yl)piperazine and benzo[b]thiophene with different substituents in 5 position (H, F, NO2, NH2, CH3 and OH) have been synthesized in order to obtain new dual antidepressant drugs. The final compounds were evaluated for in vitro 5-HT(1A) receptor affinity and serotonin reuptake inhibition by radioligand assays. Compounds 1-(5-nitrobenzo[b]thiophen-3-yl)-3-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]propan-1-ol (4c) (Ki = 6.8 for 5-HT(1A) receptor and Ki = 14 for 5-HT transporter) and 1-(5-hydroxybenzo[b]thiophen-3-yl)-3-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl] propan-1-ol (4f) (Ki = 6.2 for 5-HT(1A) receptor and Ki = 18.2 for 5-HT transporter) showed the best results for both activities.

Animals↗
PubMed1991

Sodium thiophene carboxylate does not facilitate expectoration.

A randomised double-blind crossover study compared the clinical effectiveness of a 21-day treatment with 600 mg per day of sodium thiophene carboxylate and placebo in 33 patients with stable chronic bronchial disease. During the seven week trial, subjective symptoms and findings were recorded, pulmonary function tests performed and sputum physical characteristics determined. Side-effects were closely monitored. Both subjective assessment of overall clinical efficacy and statistical analysis of the above mentioned factors failed to show any significant advantage of sodium thiophene carboxylate to placebo. Sodium thiophene carboxylate appears to be an expectorant and mucoregulatory drug, lacking evidence of clinical effectiveness in the treatment of patients with stable chronic bronchitis.

Asthma↗