Thienopyrimidine Derivatives Research Articles

A Synthesis of Novel Sulfur-Linked Fused Thienotriazolopyrimidine Derivatives

Interleukin-6 (IL-6) binds to its receptor (IL-6R, a ligandbinding 80 kDa glycoprotein chain) and induces the homodimerization of a signal transducing glycoprotein 130 (gp130), leading to the activation of the Janus kinase (Jak)/signal transducer and signal activator of transcription-3 (STAT3). STAT3 is also frequently over-expressed or persistently activated in most tumors and cancer, and activated STAT3 was found to suppress tumor-immune surveillance. Therefore, the blockade of STAT3 activation pathway stimulated by IL-6 could be an attractive therapeutic target for discovery of new drugs and is currently under intense investigation. In the other hand, thienotriazolopyrimidines have recently attracted much interest because of their pharmacological and therapeutic properties including anticancer, anti-inflammatory, urea transport protein (UT-B) inhibitor, Shiga toxin trafficking inhibitor 1, and xanthine oxidase inhibitor 2, as shown in Figure 1. Furthermore, sulfur-linked triazoles (3thio-1,2,4-triazoles) have been reported to possess a wide range of biological activities such as antifungal agent, diacylglycerol acyltransferase 1 (DGAT1) inhibitor 3, carbonic anhydrase inhibition, somatostatin sst2/sst5 agonists, and dopamine D3 receptor antagonist 4. 5 We have synthesized over the years thienopyrimidine and thienotriazolopyrimidine derivatives of promising biological activity. From a programme to discover novel inhibitors using thienopyrimidine derivatives, some of sulfur-linked thienotriazolopyrimidine compounds were recently found to possess potent IL-6/STAT3 inhibition. This result encouraged us to prepare new sulfur-linked tetracyclic thienotriazolopyrimidines in attempt to improve the IL-6/STAT3 inhibitory activity.

Identification of new novel scaffold for Aurora A inhibition by pharmacophore modeling and virtual screening.

Aurora kinases belong to family of highly conserved serine/threonine protein kinases that are involved in diverse cell cycle events and play a major role in regulation of cell division. Abnormal expression of Aurora kinases may lead to cancer; hence, these are considered as a potential target in cancer treatment. In this research article, we identified three novel Aurora A inhibitors using modern computational tools. A four-point common 3D pharmacophore hypothesis of Aurora A (AurA) inhibitors was developed using a diverse set of 55 thienopyrimidine derivatives. A three-dimensional quantitative structure-activity relationship (3D-QSAR) study was carried out using atom-based alignment of diverse set of 55 molecules to evaluate the structure- activity relationships. Docking and 3D-QSAR studies were performed with the 3D structure of AurA to evaluate the generated pharmacophore. The pharmacophore model and 3D-QSAR results complemented the results of our docking study. The pharmacophore hypothesis, which yields the best results, was used to screen the Zinc 'clean drug-like' database. Various database filters such as 3D-arrangement of pharmacophoric features, predicted activity and binding interaction score were used to retrieve hits having potential AurA inhibition activity.

Synthesis and biological evaluation of thienopyrimidine derivatives as GPR119 agonists

A series of thienopyrimidine derivatives was synthesized and evaluated for their GPR119 agonistic ability. Several thienopyrimidine derivatives containing R1 and R2 substituents displayed potent GPR119 agonistic activity. Among them, compound 5d, which is a prototype, showed good in vitro activity with an EC50 value of 3nM and human and rat liver microsomal stability. Compound 5d exhibited no CYP inhibition and induction, Herg binding, or mutagenic potential. Compound 5d showed increase insulin secretion in beta TC-6 cell and lowered the glucose excursion in mice in an oral glucose-tolerance test.

Synthesis and pharmacological evaluation of novel thienopyrimidine and triazolothienopyrimidine derivatives

Novel tricyclic thienopyrimidines (2, 3, 5, 8) and triazole-fused tetracyclic thienopyrimidines (6a–c and 9a–c) were synthesized from the precursor 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carbonitrile (1). The structures of newly synthesized compounds were established by spectral and analytical data. The title compounds were screened for analgesic, anti-inflammatory, ulcerogenicity index, and antibacterial activities. Test compounds exhibited significant activity, the compounds (6a–c) and (9a–c) showed more potent analgesic activity, and the compounds (6c) and (9c) showed more potent anti-inflammatory activity than the reference standard Diclofenac Sodium. All the synthesized compounds exhibited remarkable antibacterial activity.

Novel Thienopyrimidine Derivatives Containing 1,2,4-triazoles and 1,3,4-oxadiazoles as Potent Antimicrobial Activity

A series of thienopyrimidine oxadiazolederivatives (5a-l) were synthesized by cyclic condensation of substituted aroylhydrazides with triazole of carboxylic acid (4a-c). The synthesized compounds were characterized on the basis of their spectral (IR, 1H and 13C NMR) data and screened for antimicrobial activity where compounds 5b and 5d showed significant activity.

Antiproliferative Activity of Novel Thiophene and Thienopyrimidine Derivatives

A novel series of newly synthesized thiophene derivatives, ethyl-4,5-dimethyl-2-(3-(3,4,5-trimethoxyphenyl)thioureido)thiophene-3-carboxylate 3, ethyl-2-[(2-(dimethylamino)ethoxy)mercapto)methyleneamino)]-4,5-dimethyl-thiophene-3-carboxylate 9, thienopyrimidines 4, 7, 10-20, triazolothienopyrimidines 5, 6 were prepared and tested for their antiproliferative activity. The structures of the synthesized compounds were confirmed on the basis of elemental analysis, IR, (1)H-NMR, (13)C-NMR and mass spectral data. The results showed that the synthesized compounds were more active on breast cancer than on colon cancer cell lines and the most potent compounds in this study are compounds 3 and 13 which exerted remarkable activity against MDA-MB-231 (breast cancer) and HT-29 (colon cancer) cell lines with IC50 values (40.68, 49.22 μM) for compound 3 and (34.04, 45.62 μM) for compound 13. Also, compounds 4-6, 9 showed a moderate activity against breast cancer cell line, while compounds 15, 19 and 20 showed no activity.

ChemInform Abstract: Regioselective Metalations of Pyrimidines and Pyrazines by Using Frustrated Lewis Pairs of BF3·OEt2 and Hindered Magnesium— and Zinc—Amide Bases.

AbstractThis paper describes the regioselective electrophilic substitution of different ring positions in pyrimidine, pyrazine, and thienopyrimidine derivatives.

Synthesis and Biological Evaluation of Some Novel Thieno[2,3-d] pyrimidine Derivatives as Potential Anti-inflammatory and Analgesic Agents

A novel series of thienopyrimidine derivatives bearing various substituents or linked to various heterocyclic moieties through atoms spacers were prepared starting from 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6- carboxamide potassium salt 3. Twelve out of the prepared compounds were selected and evaluated for their antiinflammatory activity using the formalin-induced paw edema and the turpentine oil-induced granuloma pouch bioassays using diclofenac sodium as a reference standard. The ulcerogenic effects and acute toxicity (ALD50) values of these compounds were also determined. In addition, the analgesic activity of the same compounds was evaluated using the rat tail withdrawal technique. The results revealed that compounds 5a, 13, 14b, 15a, 16a and 16b had high anti-inflammatory effect comparable to diclofenac sodium, whereas compounds 5a, 14a, 15a and 16a revealed pronounced analgesic activity that is equal or higher than that of the reference. All of the tested compounds revealed high GI safety profile and were well tolerated by the experimental animals with high safety margin (ALD50 > 3.0g/Kg).

Design, Synthesis, and Antihyperlipidemic Evaluation of Novel 2‐[1‐(Substitutedphenyl)‐4‐oxo‐azetidin‐2‐yl]‐5,6‐disubstitutedthieno[2,3‐d]pyrimidin‐4(3H)‐ones

Novel thienopyrimidine derivatives of azetidinone possessing the combined features of the cholesterol absorption inhibitor drug ezetimibe and potential antihyperlipidemic 2-substitutedthienopyrimidin-4-ones were synthesized and characterized by spectroscopic data and elemental analysis. These compounds were evaluated for their lipid-lowering activity in Wistar albino rats. Some of them showed significant lipid-lowering effects comparable to those of the standard drug, gemfibrozil, at the same dose levels.

Regioselective Metalations of Pyrimidines and Pyrazines by Using Frustrated Lewis Pairs of BF3⋅OEt2 and Hindered Magnesium– and Zinc–Amide Bases

This paper describes the regioselective electrophilic substitution of different ring positions in pyrimidine, pyrazine, and thienopyrimidine derivatives.

ChemInform Abstract: Thieno[2,3‐d]pyrimidines in the Synthesis of New Fused Heterocyclic Compounds of Prospective Antitumor and Antioxidant Agents. Part 2.

AbstractA variety of new fused thienopyrimidine derivatives are synthesized from thienopyrimidinethione (I) or ‐hydrazine (IX) and evaluated for their cytotoxicity and antioxidant activity.

CoMFA and CoMSIA 3D QSAR Models for a Series of Some Condensed Thieno[2,3-d]pyrimidin-4(3H)-ones with Antihistaminic (H1) Activity

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies were carried out for a series of thienopyrimidines, novel Histamine H1 receptor antagonists. Various models were generated. The best predictive CoMFA model gave significant correlation coefficients (cross-validated r2 (q2) = 0.514, non-cross-validated r2 = 0.925), showing the influence of steric and electrostatic fields. Likewise, the best predictive CoMSIA model gave cross-validated r2 (q2) = 0.541, non-cross-validated r2 = 0.862, eliciting the influence of steric, electrostatic, hydrophobic and hydrogen bond acceptor fields. The generated models were externally validated and well correlated with calculated (predicted) and experimental inhibitory concentration (IC50) values, using test sets. The analysis of the contour maps of both CoMFA and CoMSIA models offer important structural insight for designing novel and more active Histamine H1 receptor antagonists prior to their synthesis.

Design, Synthesis and Pharmacological Evaluation of New Nonsteroidal Anti-Inflammatory Derived from 3-Aminobenzothieno[2,3-<i>d</i>]pyrimidines

During the last few years, condensed thienopyrimidine derivatives have received considerable attention. The therapeutic importance of thienopyrimidines prompted us to synthesize some of spiro(benzothieno[2,3-d]pyrimidine-4-one) derivatives. Some of the novel benzothino-pyrimidine derivatives 3a, 9b, 10b, 11a, 11b, and 11c showed considerable potent anti-inflammatory and analgesic activity of superior G.I.T. safety profile in experimental rats in comparing to indomethacin and tramadol as reference drugs.

Design, synthesis and biological evaluation of some novel thienopyrimidines and fused thienopyrimidines as anti-inflammatory agents

Some new substituted thienopyrimidine derivatives comprising thioxo, thioalkyl and pyrazolyl derivatives as well as fused thienotriazolopyrimidine and thienopyrimidinotriazine ring systems were prepared from 3-benzyl-2-hydrazino-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxamide 4. The designed compounds were evaluated for their anti-inflammatory activity. Compounds 4, 9, 10 and 13 showed the highest anti-inflammatory effect compared with the reference drug diclofenac sodium.

ChemInform Abstract: Synthesis of New 1,2,4‐Oxadiazolidin‐5‐ylthiophenes and Thienopyrimidine Derivatives by Aza‐Wittig Reaction Using a Thienyl Carbodiimide.

AbstractThe aza‐Wittig reaction of iminophosphorane (I) with phenyl isocyanate generates a highly reactive carbodiimide intermediate which undergoes 1,3‐dipolar cycloaddition with nitrone (III) to yield 1,2,4‐oxadiazolium‐5‐ylthiophene (IV).

Synthesis of new 1,2,4-oxadiazolidin-5-ylthiophenes and thienopyrimidine derivatives by aza-Wittig reaction using a thienyl carbodiimide

Abstract Azidation of aminothiophene derivative 1 afforded the corresponding azido derivative 2. The latter reacted with triphenylphosphine to afford iminophosphorane derivatives 3. Reacting 3 with phenylisocyanate gave the highly reactive carbodiimide intermediate 4, which was reacted with different nitrones to afford new 1,2,4-oxadiazolidin-5-ylidene-aminothiophenes 5a–c. Treatment of 4 with absolute EtOH at room temperature gave methyleneamino-5-(methylthio)thiophene 7, (methylthio)-3-(3-phenylureidothiophene)-2-carboxylate 8 or thienopyrimidine 9 and 10 at refluxing temperature. Finally reaction of carbodiimide intermediate 4 with different secondary amines gave the new thienopyrimidines 11a–c.

Uses of 2-Amino-5,6-dihydro-4H-cyclopenta [b] thiophene-3-carbonitrile in the Synthesis of Heterocyclic Compounds with Anticonvulsant, Behavioral and CNS Antidepressant Activities

The reaction of the cyclopenta[b]thiophene derivative 3 with phenylisothiocyanate4 gave thiourea derivative 5. The latter was reacted with the active methylene reagents 2a, b and 7 to give pyrimidine derivatives 6a, b and 8. N-Acylation of compound 3 was achieved via its reaction with acetic anhydride 9 to give the acetyl derivative 10. Compound 10 was utilized as a key for the synthesis of different heterocyclic compounds, where arylidene derivative 12 was obtained via its reaction with benzaldehyde11 and thienopyridone derivative 13 was obtained via its intramolecular cyclization using basic catalysis. Finally treatment of 10 with different activated carbonitriles2a, b or with hydrazine derivatives 15a, b afforded thienopyridone derivatives 14a,b and thienopyrimidine derivatives 17a,b, respectively. The newly synthesized compounds were tested for anticonvulsant, behavioral and CNS antidepressant activities.

ChemInform Abstract: An Efficient and Simple Route to Prospective Biologically Active Isoindoloquinazoline, Pyrimidine and Thiazine Derivatives Using 2‐Amino‐N′‐arylbenzamidine and Related Compounds as Starting Materials.

The reaction of (Z)-2-amino-N′-arylbenzamidines 1, 2-amino-4,5,6,7-tetrahydrobenzo[b]-thiophene-3-carboxamide (4) and 4-amino-5-substituted-2-(phenylamino)thiophene-3-carboxamides 12 with o-phthalaldehyde (2), terephthalaldehyde (9), and 4-formyl[2.2]paracyclophane (16) in ethanol under reflux conditions afforded isoindoloquinazoline, thienopyrimidine, pyrimidine and thiazine derivatives, respectively. The products were characterized based on their spectroscopic data and elemental analysis.

ChemInform Abstract: Design and Synthesis of Some New Thiophene, Thienopyrimidine and Thienothiadiazine Derivatives of Antipyrine as Potential Antimicrobial Agents.

AbstractA variety of hitherto unknown heterocyclic compounds incorporating the antipyrine moiety are synthesized using 4‐acetamidopyrazolone (I) as starting compound.

Convenient One-Pot Synthesis of Functionalized Thieno[3,2-d]pyrimidine and Thieno[2,3-d]pyrimidine Derivatives

A versatile one-pot method was developed for the preparation of a range of functionalized thieno[3,2-d]pyrimidine and thieno[2,3-d]pyrimidine derivatives. This protocol significantly reduces the cost and time for the synthesis of these compounds in comparison with previous routes, while facilitating scale up to multigram quantities in good yields (66-99%). The technique also permits the synthesis of bis(thienopyrimidine) derivatives not readily available by other methods.