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PubMed2004

Design, synthesis, and SAR studies of some 5-aliphatic oximino esters of thiophene as potential anti-inflammatory leads: comparative biological activity profile of aliphatic oximes vs aromatic oximes.

A series of novel tetra substituted thiophenes were synthesized, characterized, and evaluated for their anti-inflammatory activity in carrageenin induced rat paw edema model-an acute in vivo model. Compounds V1, V3, V11, V12, V17, and V18 showed good anti-inflammatory activity, indicating the importance of oxime moiety in modulating the activity. The structure-activity relationship studies explore "the aliphatic oxime esters" attached via a ketone bridge to fifth position of the thiophene, and indicate that this feature may enhance the anti-inflammatory activity as compared to aromatic oximes. Since free radicals are implicated in various inflammatory disorders, the free radical scavenging activity of some of the synthesized candidates was assessed using 1,1-diphenyl-2-picryl hydrazyl assay. The oxime containing analogs exhibited weak to moderate activity as free radical scavengers in DPPH assay. A plausible reasoning for its free radical scavenging ability is discussed. All the compounds were also screened in nitro blue tetrazolium model, to assess them as superoxide anion radical scavengers. A direct correlation between anti-inflammatory activity and free radical scavenging activity was not seen. The results disclose a new class of anti-inflammatory agents designed and synthesized for the first time wherein the utility of aliphatic oxime esters in modulating the anti-inflammatory activity profile is apparent. This will give us potential anti-inflammatory leads.

Animals↗
PubMed2005

Tetra substituted thiophenes as anti-inflammatory agents: exploitation of analogue-based drug design.

A series of 17 novel tetra substituted thiophenes was designed, synthesized, and screened for anti-inflammatory activity in carrageenin induced rat paw edema model, an acute in vivo model. The lead molecule selected was Tenidap, a dual COX/LOX inhibitor. Compounds I (43%), III (60%), IV (60%), and VIII (64%) showed moderate to good anti-inflammatory activity. The best candidate among the whole series was VIII, which gave 64% protection to the inflamed paw. The side chain of candidate VIII had resemblance to that of Romazarit, a DMARD, which was withdrawn due to its toxicity profile. A probable reason for the metabolic stability of the proposed side chain not having the possibility of generating peroxy type radicals or acrylic acid moieties, unlike Romazarit, is discussed. The biological activity exhibited by the three designed series was in the order of methyl amino series > ethyl amino series > carbethoxy amino series. The -(C=O)-CH2-COOR side chain at the fifth position as in candidate VIII, the methyl amino group at the second position, and the ester at the third position of the thiophene can be considered as a three-point pharmacophore for designing better anti-inflammatory agents. The present study is a classical example of the exploitation of an analogue based drug design, which culminated in the development of good anti-inflammatory agents that have the potential of becoming dual inhibitors.

Animals↗
PubMed2006

Synthesis and antioxidant activity evaluation of new 7-aryl or 7-heteroarylamino-2,3-dimethylbenzo[b]thiophenes obtained by Buchwald-Hartwig C-N cross-coupling.

New 7-aryl or 7-heteroarylamino-2,3-dimethylbenzo[b]thiophenes were prepared by palladium-catalyzed Buchwald-Hartwig cross-coupling of 7-bromo or 7-amino-2,3-dimethylbenzo[b]thiophenes, previously prepared by us, with substituted (4-methoxy or 3,4-dimethoxy) anilines and 3-aminopyridine or with substituted (3-methoxy or 4-cyano) bromobenzenes and 2-bromopyridine, respectively, using Pd(OAc)2, rac-BINAP or Xantphos as ligands, and Cs2CO3 as base. Their antioxidant properties were evaluated by several methods: reducing power, scavenging effect on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals, inhibition of erythrocyte hemolysis and inhibition of lipid peroxidation using the beta-carotene linoleate system. EC50 values for all the methods were determined and it was possible to establish some structure-activity relationships (SARs) based on the presence and position of different substituents on the phenyl ring (1 or 2 OMe and CN), on the presence of a pyridine ring and on the position of its nitrogen atom relative to the N-H bond.

Antioxidants↗
PubMed2005

N-Glycosyl-thiophene-2-carboxamides: effects on endothelial cell growth in the presence and absence of bFGF--a significant increase in potency using per-O-acetylated sugar analogues.

Inhibitors of endothelial cell proliferation are of interest in development of therapies for angiogenesis related disease. N-Glucosyl-thiophene-2-carboxamides have been synthesized and evaluated for their effects on proliferation in bovine aortic endothelial cells. Per-O-acetylated-N-glucosyl-thiophene-2-carboxamides showed improved inhibition of both serum and bFGF stimulated uptake of [(3)H]thymidine, when compared to non-acetylated analogues.

Acetylation↗
PubMed2006

Synthesis and antiparasitic evaluation of bis-2,5-[4-guanidinophenyl]thiophenes.

A series of bis-2,5-[4-guanidinophenyl]thiophenes were prepared in a five step process starting from 2,5-bis[trimethylstannyl]thiophene. The compounds were evaluated in vitro against Trypanosoma brucei rhodesiense (T. b. r.), Plasmodium falciparum (P. f.), Leshmania donovani (L. d.) and Trypanasoma cruzi (T. c.), and in vivo against T. b. r. Certain compounds show promising in vitro activity against T. b. r. and P. f. and have superior in vivo activity against T. b. r. to that of pentamidine and furamidine.

Animals↗
PubMed2005

Antinociceptive properties of acetylenic thiophene and furan derivatives: evidence for the mechanism of action.

The aim of the present study was to evaluate the antinociceptive potential of the acetylenic thiophene and furan derivatives: 3-(furan-2-il) prop-2-yn-1-ol 1, 1-(thiofen-2-il) pent-1yn-3-ol 2 and 4-(thiofen-2-il)-2-metilbut-3-yn-2-ol 3 on three different pain models in mice. The pain models evaluated were the acetic acid-induced writhing, capsaicin-induced pain and the tail immersion test. The possible mechanisms involved in the antinociceptive effect of these compounds were also investigated. Thus, the acetylenic thiophene and furan derivatives presented antinociceptive effect in the pain tests caused by chemical agents. Statistical analysis showed that compounds 1 and 3 increased the latency for tail withdrawal in the tail immersion test (phasic pain). Besides, the role of the opioidergic, muscarinic cholinergic and dopaminergic systems in the acetic acid-induced writhing was examined. The antinociceptive effect of compounds 2 and 3 was prevented by pretreatment with naloxone (1 mg/kg, s.c), but not by atropine (5 mg/kg, s.c) or metoclopramide (1 mg/kg, s.c). Neither naloxone nor metoclopramide prevented the antinociceptive effect caused by compound 1, while the pretreatment with atropine antagonized the antinociceptive action of this compound. The compounds 1-3 used in this study did not reveal any motor impairment to mice in the open field. The results suggest that compounds 2 and 3 induced antinociception in the abdominal writhing test and that their effects are mediated by opiodergic receptors, while the antinociceptive effect of compound 1 may involve muscarinic cholinergic receptors.

Acetic Acid↗
PubMed2006

Synthesis and radiolabeling of N-[4-[4-(2-[11C]methoxyphenyl)piperazin-1-yl]butyl]benzo[b]thiophene-2-carboxamide -- a potential radiotracer for D3 receptor imaging with PET.

FAUC346 (N-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]benzo[b]thiophene-2-carboxamide), an in vitro D(3)-selective ligand, and its normethyl derivative have been synthesized from commercially available 1-(2-substituted-phenyl)piperazines. FAUC346 has been labeled using [(11)C]methyl triflate in acetone containing aqueous NaOH (5 Eq) at -10 degrees C for 1 min, purified on semipreparative reverse-phase high-performance liquid chromatography (HPLC) and formulated as an intravenous injectable solution using a Sep-Pak Plus C(18) device. Up to 5.5 GBq of [(11)C]FAUC346 (N-[4-[4-(2-[methyl-(11)C]methoxyphenyl)piperazin-1-yl]butyl]benzo[b]thiophene-2-carboxamide), with a specific radioactivity of 45-75 GBq/micromol, could be obtained in 30-35 min, including HPLC purification and formulation starting from 44.4 GBq of [(11)C]carbon dioxide. Preliminary pharmacological evaluation of [(11)C]FAUC346 in rat brain clearly demonstrated in vivo selectivity for D(3) receptors and the absence of radiolabeled metabolite within the brain. These encouraging results, however, could not be confirmed in nonhuman primates; therefore, this radioligand does not appear to have the required pharmacological profile for a positron emission tomography probe for imaging D(3) receptors.

Animals↗
PubMed2005

Synthesis, characterization and biological activity of some transition metals with Schiff base derived from 2-thiophene carboxaldehyde and aminobenzoic acid.

Metal complexes of Schiff base derived from 2-thiophene carboxaldehyde and 2-aminobenzoic acid (HL) are reported and characterized based on elemental analyses, IR, 1H NMR, solid reflectance, magnetic moment, molar conductance and thermal analysis (TGA). The ligand dissociation as well as the metal-ligand stability constants were calculated pH metrically at 25 degrees C and ionic strength mu=0.1 (1M NaCl). The complexes are found to have the formulae [M(HL)2](X)n.yH2O (where M=Fe(III) (X=Cl, n=3, y=3), Co(II) (X=Cl, n=2, y=1.5), Ni(II) (X=Cl, n=2, y=1) and UO2(II) (X=NO3, n=2, y=0)) and [M(L)2] (where M=Cu(II) (X=Cl) and Zn(II) (X=AcO)). The molar conductance data reveal that Fe(III) and Co(II), Ni(II) and UO2(II) chelates are ionic in nature and are of the type 3:1 and 2:1 electrolytes, respectively, while Cu(II) and Zn(II) complexes are non-electrolytes. IR spectra show that HL is coordinated to the metal ions in a terdentate manner with ONS donor sites of the carboxylate O, azomethine N and thiophene S. From the magnetic and solid reflectance spectra, it is found that the geometrical structure of these complexes are octahedral. The thermal behaviour of these chelates shows that the hydrated complexes losses water molecules of hydration in the first step followed immediately by decomposition of the anions and ligand molecules in the subsequent steps. The activation thermodynamic parameters, such as, E*, DeltaH*, DeltaS* and DeltaG* are calculated from the DrTG curves using Coats-Redfern method. The synthesized ligands, in comparison to their metal complexes also were screened for their antibacterial activity against bacterial species, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus pyogones and Fungi (Candida). The activity data show that the metal complexes to be more potent/antibacterial than the parent Schiff base ligand against one or more bacterial species.

4-Aminobenzoic Acid↗
PubMed2003

Synthesis of heteroaromatic analogues of (2-aryl-1-cyclopentenyl-1-alkylidene)-(arylmethyloxy)amine COX-2 inhibitors: effects on the inhibitory activity of the replacement of the cyclopentene central core with pyrazole, thiophene or isoxazole ring.

Several heteroaromatic analogues of (2-aryl-1-cyclopentenyl-1-alkylidene)-(arylmethyloxy)amine COX-2 inhibitors, in which the cyclopentene moiety was replaced by pyrazole, thiophene or isoxazole ring, were synthesized, in order to verify the influence of the different nature of the central core on the COX inhibitory properties of these kinds of molecules. Among the compounds tested, only the 3-(p-methylsulfonylphenyl) substituted thiophene derivatives 17 and 22, showed a certain COX-2 inhibitory activity, accompanied by an appreciable COX-2 versus COX-1 selectivity. Only one of the 1-(p-methylsulfonylphenyl)pyrazole compounds (16) displayed a modest inhibitory activity towards both type of isoenzymes, while the pyrazole 1-(p-aminosulfonylphenyl) substituted 12 proved to be significantly active only towards COX-1. All the isoxazole derivatives were inactive on both COX isoforms.

Amines↗
PubMed2002

Design and synthesis of 4,5-disubstituted-thiophene-2-amidines as potent urokinase inhibitors.

A study of the S1 binding of lead 5-methylthiothiophene amidine 3, an inhibitor of urokinase-type plasminogen activator, was undertaken by the introduction of a variety of substituents at the thiophene 5-position. The 5-alkyl substituted and unsubstituted thiophenes were prepared using organolithium chemistry. Heteroatom substituents were introduced at the 5-position using a novel displacement reaction of 5-methylsulfonylthiophenes and the corresponding oxygen or sulfur anions. Small alkyl group substitution at the 5-position provided inhibitors equipotent with but possessing improved solubility.

Alkylation↗
PubMed1999

A new anti-tubulin agent containing the benzo[b]thiophene ring system.

A new type of inhibitor of tubulin polymerization was discovered based on the 3-aroyl-2-arylbenzo[b]thiophene molecular skeleton. The lead compound in this series, 2-(4'-methoxyphenyl)-3-(3',4',5'-trimethoxybenzoyl)-6-methoxybe nzo[b]thiophene 1, inhibited tubulin polymerization, caused an increase in the mitotic index of CA46 Burkitt lymphoma cells, and inhibited the growth of several human cancer cell lines.

Dose-Response Relationship, Drug↗
PubMed2002

Synthesis and biological evaluation of cyclopenta[c]thiophene related compounds as new antitumor agents.

A series of 22 cyclopenta[c]thiophene related compounds was obtained by the pharmacomodulation of 6-amino-5,6-dihydro-4H-cyclopenta[c]thiophen-4-ones 1a-g. All compounds were evaluated for potential anticancer activity in the NCI's in vitro human disease-oriented tumor cell line screening panel that consisted of 60 human tumor cell lines arranged in nine subpanels, representing diverse histologies. Among these tested compounds, seven were found to be cytotoxic, especially against leukemia cell lines, allowing us to point out some structure-activity relationships. These derivatives were further evaluated for potential in vivo anticancer activity in the hollow fiber assay developed at the NCI, which selected two compounds, 1f and 3a for standard xenograft testing.

Antineoplastic Agents↗
PubMed2006

Energy transfer in hybrids based on a thiophene-substituted ethynylbipyridine dimer decorated with Re(I), Ru(II), and Os(II) units.

The preparation, structural features, electrochemical behavior, and optical properties (at room temperature and at 77 K) are reported for a series of thiophene-containing hybrids based on the bent conjugated backbone of a rigid ditopic ligand, the dimeric moiety 3,4-dibutyl-2,5-bis{5'-[(3,4-dibutylthien-2-ylethynyl)-2,2'-bipyridin-5-yl]ethynyl}thiophene (TBTBT). Within the dimer, the diethynyl-2,2'-bipyridine units (bpy, the coordination sites) alternate with three 3,4-dibuthylthiophene units and coordination of the [Re(CO)3Cl], [Ru(bpy)2]2+, and [Os(bpy)2]2+ centers results in the mononuclear species RuTBTBT and OsTBTBT and the binuclear species RuTBTBTRu, OsTBTBTOs, RuTBTBTOs, and ReTBTBTOs. At room temperature, the emitting states obtained by photoexcitation are of 3MLCT nature, and vibronic analysis of the emission spectra indicates that they are largely delocalized over the TBTBT ligand. In the binuclear species, the intermetal separation is ca. 17 A, and for RuTBTBTOs, an efficient Ru --> Os excitation transfer takes place, resulting solely in an Os-based emission. The process is ascribed to double-electron transfer (Dexter), as mediated by the TBTBT ligand; a similar conclusion holds for the case of ReTBTBTOs. For RuTBTBTOs, the process is discussed in some detail also with regard to the possibility of disentangling the constituent hole and electron-transfer events.

Electrochemistry↗
PubMed1992

Thiophene systems. 14. Synthesis and antihypertensive activity of novel 7-(cyclic amido)-6-hydroxythieno[3,2-b]pyrans and related compounds as new potassium channel activators.

The synthesis and antihypertensive activity of novel 7-(cyclic amido)-6-hydroxy-5,5-dimethylthieno[3,2-b]pyrans and related compounds are described. The compounds were tested for oral antihypertensive activity in spontaneously hypertensive rats (SHR) and selected compounds were evaluated in vitro for increases in 86Rb efflux in rabbit isolated mesenteric arteries. The effects on activity in SHR of lactam ring size, the presence of heteroatoms in the lactam ring, the relative stereochemistry at C-6 and C-7, and the substituents on the thiophene ring are examined. The best racemic compound in this series is 32, trans-5,6-dihydro-6-hydroxy-5,5-dimethyl-2-nitro-7-(2-oxopiperidin -1-yl)-5H- thieno[3,2-b]pyran, which is 10-fold more potent than cromakalim with an ED30 = 0.015 mg/kg in SHR. Compound 32 could be resolved and the antihypertensive activity determined to reside primarily in the (6S,7S)-(-)-enantiomer 41. Surprisingly, the elimination of water to give the enamides 50-52, thiophene isosteres of bimakalim, diminishes activity significantly.

Animals↗
PubMed1991

Novel thiophene-, pyrrole-, furan-, and benzenecarboxamidotetrazoles as potential antiallergy agents.

The synthesis and antiallergic activity of a series of novel thiophene-, pyrrole-, furan-, and benzenecarboxamidotetrazoles are described. A number of compounds inhibit the release of histamine from anti-IgE-stimulated human basophils. Optimal inhibition is exhibited in compounds with a 3-alkoxy, a 4-halo, and a 5-methyl, 5-methoxy, or 5-bromo on a thiophene-2-carboxamidotetrazole.

Basophils↗
PubMed1981

Cerebrovasodilatation through selective inhibition of the enzyme carbonic anhydrase. 3. 5-(Arylthio)-, 5-(arylsulfinyl)-, and 5-(arylsulfonyl)thiophene-2-sulfonamides.

A series of 5-(arylthio)-, 5-(arylsulfinyl)-, and 5-(arylsulfonyl)thiophene-2-sulfonamides is described and anticonvulsant activities are listed for the compounds. In most cases, the sulfones had the highest activity and the sulfides the least. Sulfones with 3- or 4-halo substituents generally had the highest activity, and one analogue, 5-[(4-fluorophenyl)sulfonyl]thiophene-2-sulfonamide (51, UK-17022), had an anticonvulsant ED50 fo 2 mg/kg when administered orally to mice. Compound 51 selectively increased cerebral blood flow in animals without an unacceptable level of diuresis.

Animals↗
PubMed1986

Selective thromboxane synthetase inhibitors. 3. 1H-imidazol-1-yl-substituted benzo[b]furan-, benzo[b]thiophene-, and indole-2- and -3-carboxylic acids.

The preparation of a series of 1H-imidazol-1-yl-substituted benzo[b]furan-, benzo[b]thiophene-, and indolecarboxylic acids is described. Most of the compounds were potent inhibitors of TxA2 synthetase in vitro, and the distance between the imidazole and carboxylic acid groups was found to be important for optimal potency. The most potent compound in vivo was 6-(1H-imidazol-1-ylmethyl)-3-methylbenzo[b]thiophene-2-carboxylic acid (71), which, in conscious dogs, showed a similar profile of activity to that of dazoxiben (1).

Animals↗