2-substituted Thieno Research Articles

Discovery of (2-(pyrrolidin-1-yl)thieno[3,2-d]pyrimidin-4-yl)(3,4,5-trimethoxyphenyl)methanone as a novel potent tubulin depolymerizing and vascular disrupting agent

In this study, a series of 2-substituted thieno[3,2-d]pyrimidin-4-yl(3,4,5-trimethoxyphenyl)methanones were designed, synthesized and evaluated as novel anti-tubulin polymerization and vascular disrupting agents. A pyrrolidin-1-yl derivative, compound 20, exhibited strong antiproliferative activities (average IC50 = 13.4 nM) against four cancer cell lines. 20 also showed retained potency toward paclitaxel-resistant A549 cells. 20 could significantly inhibit tubulin polymerization with an IC50 of 1.6 μM. 20 displayed strong induction of G2/M arrest and apoptosis through the mitochondrial pathway. Dose-dependent suppression of the migration of cancer cells and the formation of a vascular network were observed after treatment with 20. The acceptable microsomal stability implied that it is worth conducting further study on the analogues of 20 as novel drug candidates of CBSIs.

Silica gel-assisted synthesis of benzo[b]thiophenes from o-(alkylsulfanyl)(ethynyl)benzenes

A variety of 2-substituted benzo[b]thiophenes were prepared from o-(alkylsulfanyl)(ethynyl)benzenes in the presence of silica gel under thermal conditions. Tertiary alkyl-substituted sulfanyl derivatives gave good results. Methylsulfanyl-substituted precursors also afforded benzo[b]thiophenes at higher temperature. Effect of modified silica gel was evaluated and the mechanism of this method was discussed. This method was also applied to preparation of 2-substituted thieno[3,2-b]thiophenes, which gave moderate yields.

Synthesis and Antibacterial and Antifungal Activity of New Thieno[2,3-d]Pyrimidin-4(3H)-One Derivatives

A series of new 2-(4/3-substitutedbenzyl)thieno[2,3-d]pyrimidin-4(3H)-ones (2a-f) and 2-(4/3-substituted benzyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one derivatives (3a-f) were synthesized for the first time by the reaction of corresponding 2-aminothiophene-3-carboxamide derivatives and appropriate iminoester hydrochlorides under suitable conditions. Using microdilution method, the antibacterial and antifungal activities of the synthesized compounds were tested against selected strains of Gram positive and Gram negative bacteria (Staphylococcus aureus, Enterecoccus faecalis, Escherichia coli and Pseudomonas aeruginosa) and yeast-like fungi (Candida albicans, C. krusei and C. parapsilosis). In these tests, compounds 3a-f showed higher antifungal activity than fluconazole against Candida fungus species. 2-Substituted thieno-[2,3-d]pyrimidin-4(3H)-ones (2a-f) showed better antibacterial activity than 2-substituted 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one derivatives (3a-f).

One-pot synthesis of 2-substituted thieno[3,2-b]indoles from 3-aminothiophene-2-carboxylates through in situ generated 3-aminothiophenes

A convenient protocol for one-pot synthesis of thieno[3,2-b]indoles, bearing aromatic, thien-2-yl or styryl fragments at C-2 position, from easily accessible 5-substituted 3-aminothiophene-2-carboxylates using the Fischer indolization reaction, was developed during this study. Two main steps of this approach are the saponification of the starting 3-aminoesters with sodium hydroxide and next treatment of the crude 3-aminoacids sodium salts with arylhydrazines in glacial acetic acid solution. The latter step includes in situ decarboxylation of the freed 3-aminothiophene-2-caboxylic acids to the 3-aminothiophenes and their acid promoted reaction with arylhydrazines to initially form arylhydrazones of 5-substituted thiophene-3(2H)-ones, which smoothly cause indolization to afford the desired thieno[3,2-b]indoles.

Divergent synthesis of 3-substituted thieno[3,4-b]thiophene derivatives via hydroxy-based transformations

Modular assembly of 3-substituted thieno[3,4-b]thiophenes: we have developed the first Pd-catalytic method to access 3-hydroxythieno[3,4-b]thiophene-2-carboxylate, which can be widely utilized for modular assembly of structurally diverse 3-substituted thieno[3,4-b]thiophene derivatives.

Thieno[2,3-d]Pyrimidine-4-Ones. Part 5.# Hydrogen Chloride Promoted Synthesis of 2-Substituted Thieno[2,3-d]Pyrimidine-4-Ones and their Structural Investigations

Synthesis of some novel 2-substituted thieno[2,3-d]pyrimidine-4-ones have been studied. It was found that in this case the 2-amino-4,5-dimethylthiophene carboxamide ( 1) can serve effective synthone for the synthesis 2-aryl-5,6-dimethyl-3,4-dihydrothieno[2,3-d]pyrimidine-4-ones ( 3-13 ). Interaction of amide 1 with substituted aromatic aldehydes in the presence of concentrated hydrochloric acid leads to the formation of compounds 3-13 . It was impossible to isolate intermediates ( 2), substances with asymmetric carbon atom in position 2. It was revealed that intermediates 2 by oxidation on air easily turn into 2-arylthieno[2,3-d]pyrimidine-4-ones. The structure of synthesized compounds was confirmed by IR- and

A new and convenient synthetic way to 2-substituted thieno[2,3-b]indoles.

A short and robust approach for the synthesis of 2-(hetero)aryl substituted thieno[2,3-b]indoles from easily available 1-alkylisatins and acetylated (hetero)arenes has been advanced. The two-step procedure includes the “aldol-crotonic” type of condensation of the starting materials, followed by treatment of the intermediate 3-(2-oxo-2-(hetero)arylethylidene)indolin-2-ones with Lawesson’s reagent. The latter process involves two sequential reactions, namely reduction of the C=C ethylidene double bond of the intermediate indolin-2-ones followed by the Paal–Knorr cyclization, thus affording tricyclic thieno[2,3-b]indoles.

Quantum chemical studies of pyrimidin-4-ones

Quantum chemical calculations of energies, electronic structures, and molecular geometries of 3,5,6-trimethylthieno[2,3-d]pyrimidin-4-one (1), tricyclic 2,3-tri-, 2,3-tetra-, and 2,3-pentamethylene-substituted 5,6-dimethylthieno[2,3-d]pyrimidin-4-ones (2—4), carboxylic acids 5—8 resulting from oxidation of compounds 1—4 at the methyl group in position 5 of thienopyrimidine, methyl esters of these acids (9—12), and products of ipso-nitration of esters (13—16) were performed in terms of the HF and DFT (B3LYP) approximations with the 3-21G basis set. Also, calculations for mixed anhydrides of nitric acid and carboxylic acids 17—20 were carried out. The possible causes of differences in the behaviors of 3-unsubstituted and 3-substituted thieno[2,3-d]pyrimidin-4-ones were discussed.

Quantum chemical studies of pyrimidin-4-ones 4.* Electronic structure and reactivity of substituted 2-oxo(thioxo)thieno[2,3-d]pyrimidin-4-ones. Mechanism of ipso-substitution of methyl group by nitro group

The quantum chemical calculations of the energies, electronic structures, and geometries for the products and intermediates of the ipso-nitration of 5,6-dimethyl-substituted 2-oxo- and 2-thioxothieno[2,3-d]pyrimidin-4-ones, as well as 6-methyl-5-nitrothieno[2,3-d]pyrimidin-4-one and 3,6-dimethyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-5-carboxylic acid formed under the action of a nitrating mixture on 5,6-dimethylthieno[2,3-d]pyrimidin-4-one and 3,5,6-trimethylthieno[2,3-d]pyrimidin-4-one, respectively, were performed in terms of the HF and DFT (B3LYP) approximations in the 3-21G basis set. Taking into account the substituent effects in the pyrimidine cycle, solvents, and prototropic tautomerism, possible reasons for the predominant ipso-substitution of the methyl group at the C(5) atom by the nitro group of the thienopyrimidine system and differences in behavior of 3-unsubstituted and 3-substituted thieno[2,3-d]pyrimidin-4-ones were considered.

NaSH in the construction of thiophene ring fused with N-heterocycles: A rapid and inexpensive synthesis of novel small molecules as potential inducers of apoptosis

A facile construction of a thiophene ring fused with N-heterocycles has been achieved via the reaction of NaSH with 2-chloro-3-alkynyl quinoxalines/pyrazines leading to novel 2-substituted thieno[2,3-b]pyrazine/quinoxaline derivatives as potential inducers of apoptosis. Some of them showed encouraging pharmacological properties when tested in zebrafish.

Pd/ligand-free synthesis of thienopyranones via Cu-catalyzed coupling-cyclization in PEG 400 under ultrasound

A greener and practical synthesis of 5-substituted thieno[2,3-c]pyran-7-ones has been achieved via Cu-catalyzed coupling-cyclization of 3-iodothiophene-2-carboxylic acid with terminal alkynes in the presence of K2CO3 in PEG 400 under ultrasound irradiation. A range of thienopyranone derivatives were synthesized by using this inexpensive and Pd- and ligand-free methodology.

Antimicrobial and Pharmacological Activities of Some 3-Substituted Thieno[3,2-d]-pyrimidin-4(3H)-one

Antimicrobial and Pharmacological Activities of Some 3-Substituted Thieno[3,2-d]-pyrimidin-4(3H)-one

SYNTHESIS OF CONDENSED DERIVATIVES OF 2-SUBSTITUTED THIENO[2,3- d ]PYRIMIDIN-4-ONES

A preparative method of synthesis of 2-substituted thieno[2,3-d]pyrimidin-4-ones involving deamination of the corresponding 3-amino derivatives by sodium nitrite in acidic medium is proposed. A possible reaction mechanism is considered. Authors: S. G. Kazaryan, A. S. Noravyan, and G. A. Gevorkyan. English Translation in Chemistry of Heterocyclic Compounds , 1999, 35 (7), pp 825-828 http://link.springer.com/article/10.1007/BF02252109

Efficient Synthesis of Thieno [2,3-<i>d</i>] Pyrimidin-4(4<i>H</i>)-ones by the Aza-Wittig Methodology

The carbodiimides 4, obtained from the aza-Wittig reaction of iminophosphorane 3 with aromatic isocyanates, reacted with aliphatic amines or alcohols to give 2-substituted thieno [2,3-d] pyrimidin-4(4H)-ones 6 in the presence of catalytic amount of sodium alkoxide in good yields.

Efficient Synthesis of Thieno [2,3-<i>d</i>] Pyrimidin-4(4<i>H</i>)-ones by the Aza-Wittig Methodology

The carbodiimides 4, obtained from the aza-Wittig reaction of iminophosphorane 3 with aromatic isocyanates, reacted with aliphatic amines or alcohols to give 2-substituted thieno [2,3-d] pyrimidin-4(4H)-ones 6 in the presence of catalytic amount of sodium alkoxide in good yields.

Zn(OAc)2 catalyzed microwave irradiated synthesis of substituted thieno[2,3-d]pyrimidin-4(3H)-one

Different Lewis acids were screened to catalyze the reaction of 2-amino-thiophene-3-carboxylate, orthoformate and aryl amine to form 2-substituted thieno[2,3-d]pyrimidin-4(3H)-one. Zn(OAc)2 was demonstrated to efficiently catalyze the reaction. 20 substituted thieno[2,3-d]pyrimidines were synthesized by adding 0.5% mol Zn(OAc)2 as catalyst under microwave irradiation.

ChemInform Abstract: Synthesis of Condensed Derivatives of 2-Substituted Thieno[2,3-d]pyrimidin-4-ones.

A preparative method of synthesis of 2-substituted thieno[2,3-d]pyrimidin-4-ones involving deamination of the corresponding 3-amino derivatives, by sodium nitrite in acidic medium is proposed. A possible reaction mechanism is considered.

Synthesis and spasmolytic action of 2-substituted thienopyrimidin-4-one derivatives.

In the search for novel compounds to treat disorders of smooth muscle function, efforts have focused on some 2-substituted thieno[2,3-d]pyrimidin-4-one derivatives that show interesting spasmolytic action. Our laboratories have developed a new series of quaternary salts of 2-substituted thieno[2,3-d]pyrimidin-4-one and thieno[3,2-d]pyrimidin-4-one isomers with therapeutic potential. Thesesubstances were prepared starting from simple derivatives of thiophene. Their spasmolytic activity was evaluated on transmurally stimulated guinea-pig ileum. The most active compounds (IC50 1.12-2.71 microM) 7f-7h, 12d and 12f had the terminal piperidino nucleus in the thioalkyl chain and lacked two methyl groups in the thiophene ring. Their relaxant activity on the isolated ileum was potentiated (approx. 20-25%) by phosphodiesterase inhibitors. Compounds 7f-h, 12d and 12f were less effective in inhibiting contractions of the guinea-pig ileum induced by acetylcholine (IC50 26.7-41.4 microM) or histamine (IC50 41.5-63.4 microM) and had a moderate binding activity to muscarinic receptors in membrane homogenates from the rat heart (M2 sites; pKi values between 5.55+/-0.08 and 5.14+/-0.12; n = 3) and submaxillary gland (M3 sites; pKi values between 6.15+/-0.07 and 5.76+/-0.08; n = 3). Action involving soluble guanylyl cyclase or any potential binding to guinea-pig ventricular L-type calcium channels was not considered likely. It is concluded that at least two different mechanisms of action contribute to their spasmolytic activity.

Facile synthesis of 3-substituted thieno[3,2- b]furan derivatives

A facile synthesis of dimethyl 3-hydroxythieno[3,2- b]furan-2,5-dicarboxylate is reported from the available methyl thioglycolate and dimethyl acetylenedicarboxylate starting materials. This compound represents an efficient precursor for the synthesis of 3-substituted thieno[3,2- b]furan derivatives.

Synthesis and Cycloaddition Reaction of 3‐Vinylthieno[3,2‐b][1]benzothiophene.

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