- Discovery of potent dual egfr/her2 inhibitors based on thiophene scaffold targeting h1299 lung cancer cell line
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Dual targeting of epidermal growth factor receptor (EGFR) and human EGFR-related receptor 2 (HER2) is a proven approach for the treatment of lung cancer. With the aim of discov-ering effective dual EGFR/HER2 inhibitors targeting non-small cell lung cancer cell line H1299, three series of thieno[2,3-d][1,2,3]triazine and acetamide derivatives were designed, synthesized, and biologically evaluated. The synthesized compounds displayed IC50 values ranging from 12 to 54 nM against H1299, which were superior to that of gefitinib (2) at 40 μM. Of the synthesized com-pounds, 2-(1H-pyrazolo[3,4-b]pyridin-3-ylamino)-N-(3-cyano4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (21a) achieved the highest in vitro cytotoxic activity against H1299, with an IC50 value of 12.5 nM in situ, and 0.47 and 0.14 nM against EGFR and HER2, respectively, values comparable to the IC50 of the approved drug imatinib (1). Our synthesized compounds were promising, demonstrating high selectivity and affinity for EGFR/HER2, especially the hinge region forming a hydrophobic pocket, which was mediated by hydrogen bonding as well as hydrophobic and electrostatic inter-actions, as indicated by molecular modeling. Moreover, the designed compounds showed good affinity for T790M EGFR, one of the main mutants resulting in acquired drug resistance. Furthermore, both pharmacokinetic and physicochemical properties of the designed compounds were within the appropriate range for human usage as predicted by the in Silico ADME study. The designed compound (21a) might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR/HER2.
- Elrayess, Ranza,Abdel Aziz, Yasmine M.,Elgawish, Mohamed Saleh,Elewa, Marwa,Yassen, Asmaa S. A.,Elhady, Sameh S.,Elshihawy, Hosam A.,Said, Mohamed M.
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- Synthesis, characterization, and dyeing performance of some azo thienopyridine and thienopyrimidine dyes based on wool and nylon
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A string of novel heterocyclic mono azo dyes were synthesized and their utilization in dyeing different fabrics as wool and nylon were discussed. Thienopyridine azo dyes 4 and 6were prepared by reaction of chloro acetamidederivative 2 with diamino compounds to yield 3 and 5, followed by reaction with NaNO2/HCl and coupling with nucleophilic reagent. One-pot reaction of chloro acetamide 2 with ammonium thiocyanat in solvent ethanol gave the unexpected thienopyrimidine derivative 7, which contain two active sites, the former is primary amine that was able to form diazonium salt that coupled with N,N-dimethylaniline, resorcinol, and/or self-coupling to afford the azo dyes 8-10, and the latter is active methylene group that underwent coupling with different diazonium salts to give the azo thienopyrimidine derivative dye 11-15. The dyeing performance of these azo dyes had been investigated in terms of their dyeing behavior and fastness properties on different fabrics. Results showed that the color strength (K/S) values, as well as, washing, rubbing, and resistance to acid, alkali and light showed high efficiency of these heterocyclic mono azo dyes to dye wool rather than nylon fibers.
- Regal, Mohsen K. A.,Rafat, El-Hady,El-Sattar, Nour E. A. Abd
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- Synthesis and cytotoxicity of novel thiophene, pyran and pyridine derivatives
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The reaction of 2-amino-3-cyano-tetrahydrobenzothiophene 3 with ethyl acetoacetate gave the amide derivatives 5. The reactivity of 5 toward a variety of chemical reagents was studied to give pyrans, pyridines, thiophenes and the thiazoles and their fused derivatives. The structures of the newly synthesized products were confirmed on the basis of their respective analytical and spectral data. The antitumor evaluations of the synthesized compounds against the three cancer cell lines MCF-7, NCI-H460 and SF-268 showed that compounds 9a, 9c, 12a and 14 were of the highest potencies against the three cancer cell lines among the tested compounds.
- Wardakhan, Wagnat W.,Samir, Eman M.,El-Arab, Elham E.
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- Pharmacophore modeling, 3D-QSAR, synthesis, and anti-lung cancer evaluation of novel thieno[2,3-d][1,2,3]triazines targeting EGFR
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Two series of thieno[2,3-d][1,2,3]triazine derivatives were designed, synthesized, and biologically evaluated as potential epidermal growth factor receptor (EGFR) inhibitors targeting the non-small-cell lung cancer cell line H1299. Most of the synthesized compounds displayed IC50 values ranging from 25 to 58 nM against H1299, which are superior to that of gefitinib (40 μM). 3-(5,6,7,8-Tetrahydro-7H-cyclohexa[4:5]thieno[2,3-d]-1,2,3-triazin-4-ylamino)benzene-1,3-diamine (6b) achieved the highest cytotoxic activity against H1299 with an IC50 value of 25 nM; it had the ability to decrease the EGFR concentration in H1299 cells from 7.22 to 2.67 pg/ml. In vitro, the IC50 value of compound 6b was 0.33 nM against EGFR, which is superior to that of gefitinib at 1.9 nM and erlotinib at 4 nM. The three-dimensional quantitative structure–activity relationships and molecular modeling studies revealed comparable binding modes of compound 6b, gefitinib, and erlotinib in the EGFR active site. The in silico ADME (absorption, distribution, metabolism, and excretion) prediction parameters of this compound revealed promising pharmacokinetic and physicochemical properties. Moreover, DFT (density functional theory) calculations showed the high reactivity of compound 6b toward the EGFR compared with other compounds. The designed compound 6b might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR.
- Abdel Aziz, Yasmine M.,Elewa, Marwa,Elgawish, Mohamed S.,Elrayess, Ranza,Elshihawy, Hosam A.,Said, Mohamed M.
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- Synthesis of novel 5-aryl/hetarylidenyl 3-(2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-2-thioxothiazolidin-4-ones
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The synthesis of a variety of novel 5-substituted titled compounds containing a priviledged rhodanine scaffold is described. The synthesis involves a microwave (MW) assisted Knoevenagel condensation of 3-(2-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-2-thioxothiazolidin-4-one with suitably substituted aromatic aldehydes. However, these condensations fail with aliphatic aldehydes. The 2-thioxothiazolidin-4-one (rhodanine) precursor was prepared by the condensation of 2-thioxothiazolidin-4-one-di-(carboxymethyl)trithiocarbonyl and 4,5,6,7-tetrahydrobenzo[4,5]thienyl[2,3-d]-2-methylpyrimidin-4-amine in the presence of K2CO3.
- Mendoza, Kimberly,Kamila, Sukanta,Biehl, Edward R.
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- Green synthesis of biologically important 2-aminothiophenes by the mediation of ZnO@SiO2–NH2 nanoparticle as an important anti-liver cancer alternative for valproate
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Liver cancer is one of the most important cancers that easily affects many organs in the body. Valproate is a well-known branched fatty acid and is commonly used as an antiepileptic in liver cancer therapy. Similar to many drugs, this chemical drug can induce fulminant liver failure in patients with liver cancer. So, finding new therapeutic agents with fewer side effects is of great attention. This study explains synthesis and characterization of a new effective nanocatalyst ZnO@SiO2–NH2, which can be a suitable candidate for valproate. The prepared nanocatalyst was characterized by FT-IR, TEM, XRD and FE-SEM and formation of?the desired nanoparticles with a medium grain size of 70–90?nm is justified. Then, the synthesized nanocatalyst is checked in the multi-component synthesis of some important model drugs involving substituted 2-aminothiophenes, as effective compounds against human liver cancer. The present methodology showed good generality and wide scope, nearly short span of time, good yield, easy workup and environmental friendly conditions for the preparation of the target compounds. At the final part of this study, the in?vitro cytotoxicity potential of the prepared nanoparticle is investigated against a well-known human cancer cell line HepG2 via the MTT assay. The experiments reveal that ZnO@SiO2–NH2 nanoparticles have significant cytotoxicity towards the selected cell line. As a result, although ZnO@SiO2–NH2 can be used to treat liver cancer cells, however, this nanoparticle can be utilized to synthesize 2-aminothiophenes, as effective anti-liver cancer drugs like valproate.
- Gao, Feng,Yang, Jihong,Geng, Yan,Liu, Bo,Zhang, Rui,Zhang, Meng
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p. 2647 - 2654
(2021/01/29)
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- Design, synthesis and biological evaluation of novel (E)-2-benzylidene-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)hydrazine-1-carboxamide derivatives as α-glucosidase inhibitors
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In this present study, a series of novel (E)-2-benzylidene-N-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)hydrazine-1-carboxamide derivatives against α-glucosidase were designed and synthesized, and their biological activities were evaluated in vitro and in vivo. Most of the designed analogues exhibited better inhibitory activity than the marketed acarbose, especially the most potent compound 7 with an IC50 value of 9.26 ± 1.84 μM. The direct binding of 7 and 8 with α-glucosidase was confirmed by fluorescence quenching experiments, and the kinetic and molecular docking studies revealed that 7 and 8 inhibited α-glucosidase in a non-competitive manner. Cytotoxicity bioassay indicated compounds 7 and 8 were non-toxic towards LO2 and HepG2 at 100 μM. Furthermore, both compounds were demonstrated to have in vivo hypoglycemic activity by reducing the blood glucose levels in sucrose-treated rats.
- Fang, Lei,Jiang, Cheng-Shi,Li, Yue,Song, Zhiling,Wang, Kai-Ming,Xie, Hong-Xu,Zhang, Jin-He,Zhang, Juan,Zhu, Kong-Kai
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supporting information
(2021/10/20)
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- Discovery of novel tetrahydrobenzo[b]thiophene-3-carbonitriles as histone deacetylase inhibitors
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The discovery and development of isoform-selective histone deacetylase (HDAC) inhibitor is a challenging task because of the sequence homology among HDAC enzymes. In the present work, novel tetrahydro benzo[b]thiophene-3-carbonitrile based benzamides were designed, synthesized, and evaluated as HDAC inhibitors. Pharmacophore modeling was our main design strategy, and two novel series of tetrahydro benzo[b]thiophene-3-carbonitrile derivatives with piperidine linker (series 1) and piperazine linker (series 2) were identified as HDAC inhibitors. Among all the synthesised compounds, 9h with 4-(aminomethyl) piperidine linker and 14n with piperazine linker demonstrated good activity against human HDAC1 and HDAC6, respectively. Both the compounds also exhibited good antiproliferative activity against several human cancer cell lines. Both these compounds (9h and 14n) also induced cell cycle arrest and apoptosis in U937 and MDA-MB-231 cancer cells. Overall, for the first time, this research discovered potent isoform-selective HDAC inhibitors using cyclic linker instead of the aliphatic chain and aromatic ring system, which were reported in known HDAC inhibitors.
- Gediya, Piyush,Vyas, Vivek K.,Carafa, Vincenzo,Sitwala, Nikum,Della Torre, Laura,Poziello, Angelita,Kurohara, Takashi,Suzuki, Takayoshi,Sanna, Vinod,Raguraman, Varalakshmi,Suthindhiran,Ghosh, Debarpan,Bhatia, Dhiraj,Altucci, Lucia,Ghate, Manjunath D.
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- Discovery of thieno[2,3-d]pyrimidine-based derivatives as potent VEGFR-2 kinase inhibitors and anti-cancer agents
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Vascular endothelial growth factor-2 (VEGFR-2) is considered one of the most important factors in tumor angiogenesis, and consequently a number of anticancer therapeutics have been developed to inhibit VEGFR-2 signaling. Accordingly, eighteen derivatives of thieno[2,3-d]pyrimidines having structural characteristics similar to VEGFR-2 inhibitors were designed and synthesized. Anticancer activities of the new derivatives were assessed against three human cancer cell lines (HCT-116, HepG2, and MCF-7) using MTT. Sorafenib was used as positive control. Compounds 17c-i, and 20b showed excellent anticancer activities against HCT-116 and HepG2 cell lines, while compounds 17i and 17g was found to be active against MCF-7 cell line. Compound 17f exhibited the highest cytotoxic activities against the examined cell lines, HCT-116 and HepG2, with IC50 values of 2.80 ± 0.16 and 4.10 ± 0.45 μM, respectively. Aiming at exploring the mechanism of action of these compounds, the most active cytotoxic derivatives were in vitro tested for their VEGFR-2 inhibitory activity. Compound 17f showed high activity against VEGFR-2 with an IC50 value of 0.23 ± 0.03 μM, that is equal to that of reference, sorafenib (IC50 = 0.23 ± 0.04 μM). Molecular docking studies also were performed to investigate the possible binding interactions of the target compounds with the active sites of VEGFR-2. The synthesized compounds were analyzed for their ADMET and toxicity properties. Results showed that most of the compounds have low to very low BBB penetration levels and they have non-inhibitory effect against CYP2D6. All compounds were predicted to be non-toxic against developmental toxicity potential model except compounds 17b and 20b.
- El-Metwally, Souad A.,Abou-El-Regal, Mohsen M.,Eissa, Ibrahim H.,Mehany, Ahmed B.M.,Mahdy, Hazem A.,Elkady, Hazem,Elwan, Alaa,Elkaeed, Eslam B.
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- Novel tetrahydrobenzo[b]thiophen-2-yl)urea derivatives as novel α-glucosidase inhibitors: Synthesis, kinetics study, molecular docking, and in vivo anti-hyperglycemic evaluation
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α-Glucosidase inhibitors, which can inhibit the digestion of carbohydrates into glucose, are one of important groups of anti-type 2 diabetic drugs. In the present study, we report our effort on the discovery and optimization of α-glucosidase inhibitors with tetrahydrobenzo[b]thiophen-2-yl)urea core. Screening of an in-house library revealed a moderated α-glucosidase inhibitors, 5a, and then the following structural optimization was performed to obtain more efficient derivatives. Most of these derivatives showed increased inhibitory activity against α-glucosidase than the parental compound 5a (IC50 of 26.71 ± 1.80 μM) and the positive control acarbose (IC50 of 258.53 ± 1.27 μM). Among them, compounds 8r (IC50 = 0.59 ± 0.02 μM) and 8s (IC50 = 0.65 ± 0.03 μM) were the most potent inhibitors, and showed selectivity over α-amylase. The direct binding of both compounds with α-glucosidase was confirmed by fluorescence quenching experiments. Kinetics study revealed that these compounds were non-competitive inhibitors, which was consistent with the molecular docking results that compounds 8r and 8s showed high preference to bind to the allosteric site instead of the active site of α-glucosidase. In addition, compounds 8r and 8s were not toxic (IC50 > 100 μM) towards LO2 and HepG2 cells. Finally, the in vivo anti-hyperglycaemic activity assay results indicated that compounds 8r could significantly decrease the level of plasma glucose and improve glucose tolerance in SD rats treated with sucrose. The present study provided the tetrahydrobenzo[b]thiophen-2-yl)urea chemotype for developing novel α-glucosidase inhibitors against type 2 diabetes.
- Hao, Gui-Zhou,Jiang, Cheng-Shi,Li, Yue,Liu, Shan-Kui,Xie, Hong-Xu,Zhang, Jie,Zhang, Jin-He,Zhang, Juan,Zheng, Hua,Zhu, Kong-Kai
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- Synthesis and biological evaluation of novel hybrid compounds derived from gallic acid and the 2-aminothiophene derivatives
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Abstract: Gallic acid (GA) and its benzamide derivatives have a wide variety of biological activities, such as antimicrobial, antioxidant, anticancer. In this study, we have reported the synthesis of some new hybrid compounds comprised of the 2-aminothiophene and GA moieties and evaluation of their cytotoxic activities against HeLa (cervical cancer), HCT116 (human colon cancer), and FT (fibroblast) cell lines as well as antimicrobial activities against some Gram-positive and Gram-negative bacteria. The reaction of some 2-aminothiophene derivatives (previously prepared from the Gewald reaction) with galloyl chloride having the acetylated hydroxyl groups and the subsequent deprotection of the hydroxyl groups gave the desired hybrid compounds. Then, the antimicrobial activity of the compounds was evaluated using disc diffusion and minimum inhibitory concentration assays. Finally, the MTT assay was carried out to evaluate the cytotoxicity of the synthesized compounds on the mentioned cell lines. The structure of the synthesized compounds was elucidated by conventional spectroscopic methods such as NMR, FT-IR, and UV–Vis spectroscopy. All compounds prevented the growth of Staphylococcus coagulase more than the positive control of chloramphenicol, and one compound was more sensitive to the growth of Klebsiella pneumonia compared to the standard antibiotic. All compounds showed acceptable activity against cancer cells. The highest activity was observed against HeLa with an IC50 value of 3.2 μg/mL for compound 3d and against HCT116 with IC50 of 59.4 μg/mL for 3b. The high anticancer activity of compound 3d against HeLa allows us to consider it as a good lead compound for the development of new potent anticancer agents for the treatment of cervical cancer. Graphic abstract: [Figure not available: see fulltext.]
- Falanji, Farahnaz,Hosseyni-Tabar, Seyed Mahmood,Mahdavi, Behnam,Rezaei-Seresht, Esmail,Rezaei-Seresht, Hasan
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p. 809 - 815
(2020/03/11)
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- Structure-Guided Optimization of Inhibitors of Acetyltransferase Eis from Mycobacterium tuberculosis
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The enhanced intracellular survival (Eis) protein of Mycobacterium tuberculosis (Mtb) is a versatile acetyltransferase that multiacetylates aminoglycoside antibiotics abolishing their binding to the bacterial ribosome. When overexpressed as a result of promoter mutations, Eis causes drug resistance. In an attempt to overcome the Eis-mediated kanamycin resistance of Mtb, we designed and optimized structurally unique thieno[2,3-d]pyrimidine Eis inhibitors toward effective kanamycin adjuvant combination therapy. We obtained 12 crystal structures of enzyme-inhibitor complexes, which guided our rational structure-based design of 72 thieno[2,3-d]pyrimidine analogues divided into three families. We evaluated the potency of these inhibitors in vitro as well as their ability to restore the activity of kanamycin in a resistant strain of Mtb, in which Eis was upregulated. Furthermore, we evaluated the metabolic stability of 11 compounds in vitro. This study showcases how structural information can guide Eis inhibitor design.
- Punetha, Ankita,Ngo, Huy X.,Holbrook, Selina Y. L.,Green, Keith D.,Willby, Melisa J.,Bonnett, Shilah A.,Krieger, Kyle,Krieger, Kyle,Dennis, Emily K.,Posey, James E.,Parish, Tanya,Parish, Tanya,Tsodikov, Oleg V.,Tsodikov, Oleg V.,Garneau-Tsodikova, Sylvie,Garneau-Tsodikova, Sylvie
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p. 1581 - 1594
(2020/06/05)
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- Synthesis, conformational analysis, infrared, raman and uv-visible spectra of novel schiff bases compiled with DFT calculations
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Objective: Two novel Schiff bases named, 2-((2-Hydroxybenzylidene)amino)-4,5,6,7-tetrahydrobenzo[b] thiophene-3-carbonitrile (BESB1) and 2-((Furan-2-ylmethylene)amino)-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carbonitrile (BESB2) were synthesized. Methods: The structures were characterized based on CHN elemental analysis, mid-infrared (400– 4000 cm-1), Raman (100–4000 cm-1),1H NMR, mass and UV-Vis spectroscopic measurements. In addition, quantum mechanical calculations using DFT-B3LYP method at 6-31G(d) basis set were carried out for both Schiff bases. Initially, we have carried out complete geometry optimizations followed by frequency calculations for the proposed conformational isomers; BESB1 (A–E) and BESB2 (F–J) based on the orientations of both CN and OH groups against the azomethine lone-pair (NLP) in addition to the 3D assumption. Results: The computational outcomes favor conformer A for BESB1 in which the C≡N and OH moieties are cis towards the NLP while conformer G is preferred for BESB2 (the C≡N/furan-O are cis/trans towards the NLP) which was found consistent with the results of relaxed potential energy surface scan. Aided by normal coordinate analysis of the Cartesian coordinate displacements, we have suggested reliable vibrational assignments for all observed IR and Raman bands. Moreover, the electronic absorption spectra for the favored conformers were predicted in DMSO solution using TD-B3LYP/6-31G(d) calculations. Similarly, the1H NMR chemical shifts were also estimated using GIAO approach implementing PCM including solvent effects (DMSO-d6). Conclusion: Proper interpretations of the observed electronic transition, chemical shifts, IR and Raman bands were presented in this study.
- Ahmed, Samy M.,Shaaban, Ibrahim A.,El-Mossalamy, Elsayed H.,Mohamed, Tarek A.
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p. 568 - 586
(2020/08/24)
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- Design and synthesis of novel tranilast analogs: Docking, antiproliferative evaluation and in-silico screening of TGFβR1 inhibitors
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The discovery of the antiproliferative potential of tranilast prompted additional studies directed at understanding the mechanisms of tranilast action. Its inhibitory effect on cell proliferation depends principally on the capacity of tranilast to interfere with transforming growth factor beta (TGFβR1) signaling. This work summarizes design, synthesis and biological evaluation of sixteen novel tranilast analogs on different tumors such as PC-3, HepG-2 and MCF-7 cell lines. The in vitro cytotoxicity was evaluated using MTT assay showed that, twelve compounds out of sixteen showed higher cytotoxic activities (IC50’s 1.1–6.29 μM), than that of the reference standard, 5-FU (IC50 7.53 μM). The promising cytotoxic hits (4b, 7a, b and 14c-e), proved to be selective to cancer cells when their cytotoxicity's are examined on human normal cell line (WI-38). Then they are investigated for their possible mode of action as TGFβR1 inhibitors; remarkable inhibition of TGFβR1 by these hits was observed at the range of IC50 0.087–3.276 μM. The cell cycle analysis of the most potent TGFβR1 inhibitor, 4b revealed cell cycle arrest at G2/M phase on prostate cancer cells. Additionally, it is clearly indicated apoptosis induction at Pre-G1 phase, this is substantiated by significant increase in the expression on the tumor suppressor gene, p53 and up regulation the level of apoptosis mediator, caspase-3. In addition, in silico study was performed for validating the physicochemical and ADME properties which revealed that, all compounds are orally bioavailable with no side effects complying with Lipinski rule. The proposed mode of action can be further explored on the light of molecular modeling simulation of the most potent compounds, 4b and 14e which were docked into the active sites of TGFβR1 to predict their affinities toward the receptor.
- Ismail, Magda M.F.,El-Zahabi, Heba S.A.,Ibrahim, Rabab S.,Mehany, Ahmed B.M.
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- A Microwave-Enhanced Synthesis and Biological Evaluation of N-Aryl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amines
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A series of N-aryl-5,6,7,8-tetra-hydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amines were synthesized in moderate to good yield by using a microwave-enhanced conditions. The selected compounds were evaluated for their cytotoxic effects (IC50 values) on human pulmonary carcinoma (A549), murine BALB/c spontaneous colon adenocarcinoma (CT26) and human hepatocellular liver carcinoma (HepG2) cell lines in vitro. Amongst these compounds, one compound was found to have the better cytotoxic activity with reference to the standard Erlotinib hydrochloride (TarcevaTM) against A549 (IC50 = 16.06 ± 0.09 μM) and HepG2 (IC50 = 15.01 ± 0.31 μM) cell lines. Especially, two compounds showed best cytotoxic effects against CT26 (IC50 = 11.38 ± 0.44 μM) and HepG2 (IC50 = 8.51 ± 0.52 μM) cell lines, respectively. The preliminary structure-activity relationships were disclosed and the thieno[2,3-d]pyrimidine skeleton could be exploited to potential antitumor agents in the future.
- Han, Qing,Yin, Zijian,Sui, Jingjiao,Wang, Qingming,Sun, Yaquan
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p. 1483 - 1497
(2019/08/26)
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- Design, synthesis and anticancer evaluation of thieno[2,3-d]pyrimidine derivatives as dual EGFR/HER2 inhibitors and apoptosis inducers
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Deregulation of many kinases is directly linked to cancer development and the tyrosine kinase family is one of the most important targets in current cancer therapy regimens. In this study, we have designed and synthesized a series of thieno[2,3-d]pyrimidine derivatives as an EGFR and HER2 tyrosine kinase inhibitors. All the synthesized compounds were evaluated in vitro for their inhibitory activities against EGFRWT; and the most active compounds that showed promising IC50 values against EGFRWT were tested in vitro for their inhibitory activities against mutant EGFRT790M and HER2 kinases. Moreover, the antitumor activities of these compounds were tested against four cancer cell lines (HepG2, HCT-116, MCF-7 and A431). Compounds 13g, 13h and 13k exhibited the highest activities against the examined cell lines with IC50 values ranging from 7.592 ± 0.32 to 16.006 ± 0.58 μM comparable to that of erlotinib (IC50 ranging from 4.99 ± 0.09 to 13.914 ± 0.36 μM). Furthermore, the most potent antitumor agent (13k) was selected for further studies to determine its effect on the cell cycle progression and apoptosis in MCF-7 cell line. The results indicated that this compound arrests G2/M phase of the cell cycle and it is a good apoptotic agent. Finally, molecular docking studies showed a good binding pattern of the synthesized compounds with the prospective target, EGFRWT and EGFRT790M.
- Elmetwally, Souad A.,Saied, Khaled F.,Eissa, Ibrahim H.,Elkaeed, Eslam B.
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- Design, synthesis, and cytotoxicity screening of 5-aryl-3-(2-(pyrrolyl) thiophenyl)-1, 2, 4-oxadiazoles as potential antitumor molecules on breast cancer MCF-7 cells
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The work representing the design and the cytotoxic screening of synthetic small molecules (SSMs) such as carbonitriles 3a-c, carboximidamides 4a-c, and oxadiazoles 5–19 as antitumor molecules. Molecules 4c, 9, 12, and 14 show promising cytotoxicity profiles against two cell lines higher than prodigiosin (PG). The results of topoisomerase enzyme inhibition assay show that compounds 4c and 14 display potent inhibitory activity in nano-molar concentration. In addition, DNA-flow cytometry and annexin V analysis also display that compounds 4c, 9, 12, and 14 exhibit antiproliferative activities over MCF-7 cells by cell cycle arrest at G1 phase and apoptosis-inducing activity by increasing cell percentages at pre G1 phase. Moreover, Elisa measurement of p53 and apoptosis mediators, show that carboximidamide 4c and oxadiazoles 9, 12, and 14 significantly up-regulate p53 and cell death mediators as puma and Bax/Bcl-2 ratio levels. Subsequently, pro-apoptotic activities are confirmed by active caspase 3/7 percentages green fluorescence assay.
- Abd el hameid, Mohammed K.,Mohammed, Manal R.
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p. 609 - 623
(2019/02/26)
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- 4,5,6,7-tetrahydrobenzothiophene compound application
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The invention provides an application of a 4,5,6,7-tetrahydrobenzothiophene compound, in particular to an application of a compound with a structure in a formula (I) in preparing a beta-N-acetylhexosaminidase OfHex1 inhibitor. The invention provides that the compound with the structure in the formula (I) has a better inhibiting effect on the beta-N-acetylhexosaminidase OfHex1, can be used for pestcontrol, and has easily available raw materials and less synthesis difficulty, and can be used for industrial development.
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Paragraph 0011
(2019/10/29)
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- Design, synthesis, biological evaluation and molecular modeling study of new thieno[2,3-d]pyrimidines with anti-proliferative activity on pancreatic cancer cell lines
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Pancreatic cancer is one of the most challenging diseases with seven months only as median survival time due to its poor prognosis. Several enzymes are blamed for the progress of pancreatic cancer especially, platelet-derived growth factor receptors (PDGFRs), this in turn makes them promising targets for its treatment. In this study, twenty eight new compounds based on thieno[2,3-d]pyrimidine scaffold were synthesized as anti-pancreatic cancer agents mimicking the benzofuro[3,2-d]pyrimidine derivative, amuvatinib. Various linkers including amides, esters, ketones, urea and thiourea derivatives were utilized to study their effect on the anti-proliferative activity of these compounds. Most of the tested compounds revealed good cytotoxic activities against pancreatic carcinoma cell line PANC-1. Compound 9d showed the highest cytotoxicity with an IC50 value of 5.4 μM. Furthermore, 9d showed excellent platelet derived growth factor receptor (PDGFR-α) inhibitory activity, with IC50 value 0.155 μM. Docking study was carried out into PDGFR-α active site which showed comparable binding mode to that of FDA approved PDGFR-α inhibitor, imatinib. 3D-Quantitative structure activity relationship (QSAR) model was built up with five-featured pharmacophore which could be implemented for emerging effective lead structures. These compounds could serve as a new chemotype for discovering new agents for pancreatic cancer therapy.
- Salem, Mohamed S.H.,Abdel Aziz, Yasmine M.,Elgawish, Mohamed S.,Said, Mohamed M.,Abouzid, Khaled A.M.
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- Ethylene diamine grafted nanoporous UiO-66 as an efficient basic catalyst in the multi-component synthesis of 2-aminithiophenes
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This study demonstrates ED-UiO-66 as a novel and effective solid nanoporous basic catalyst prepared through the amine grafting onto the pores of UiO-66. The manufactured nanoparticles were identified by FT-IR, XRD, TGA, FESEM, TEM, CHN and BET and the characterization results certified formation of a single phase nanoporous substance with the medium grain size less than 90?nm. The synthesized material was employed as an efficient catalyst for the preparation of 2-aminotiophenes through the Gewald method. This thermochemically stable nanocatalyst was environmentally safe, reusable and economic. Therefore, this methodology can be simply extended for industrial goals.
- Erfaninia,Tayebee,Dusek,Amini
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- 2-aminothiophene compound preparation method
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The invention discloses a 2-aminothiophene compound preparation method. The method includes the step that ketone, nitrile and sulfur in a mole ratio of 1:1:1 are used as raw materials for preparing 2-aminothiophene compounds through catalytic cyclization. By adoption of ketone, nitrile and sulfur as the raw materials, the method has advantages of simple operating steps, high product yield, low cost and the like, and a high industrial value is achieved.
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Paragraph 0031; 0032
(2019/01/14)
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- Facile pathway for synthesis of two efficient catalysts for preparation of 2-aminothiophenes and tetrahydrobenzo[b]pyrans
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Abstract: We report here a new magnetically recyclable catalyst consisting of iron-substituted Keggin-type heteropolyacid (HPA) grafted on modified Fe3O4 nanoparticles. The synthesized hybrid nanomaterial exhibited the excellent catalytic efficiency in condensation reaction for the preparation of tetrahydrobenzo[b]pyrans under solvent-free conditions as well as in the synthesis of 2-aminothiophenes via Gewald reaction. It must be noted that, HPA supported magnetite nanoparticles catalyzed the preparation of tetrahydrobenzo[b]pyrans, whereas for Gewald reaction amine-functionalized magnetite nanoparticles acted as a catalyst. Different characterization techniques such as Fourier transform infrared (FT-IR), X-ray powder diffraction (XRD), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM) and vibrating sample magnetometer (VSM) were used to characterize the hybrid nanomaterial. The reusability of catalyst was affirmed by using in consecutive runs for five times. Performance of prepared catalyst was compared with the various previously reported catalysts; the newly synthesized catalysts found to be most efficient with regard to reaction time, yield and ease of catalyst separation. Graphical Abstract: [Figure not available: see fulltext.].
- Saadati-Moshtaghin, Hamid Reza,Zonoz, Farrokhzad Mohammadi
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p. 2195 - 2213
(2017/12/18)
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- Preparation of magnetically recyclable ZnFe2O4 nanoparticles by easy single-step co-precipitation method and their catalytic performance in the synthesis of 2-aminothiophenes
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In this work, a new synthetic route for the preparation of ZnFe2O4 nanoparticles through the chemical co-precipitation using Fe2+ and Fe3+ ions in an alkaline solution was developed. The synthesized nanoparticles were characterized by XRD, FTIR, SEM, ICP-MS, DRS, TGA, VSM and elemental analysis. Characterization results confirmed the formation of single ZnFe2O4 phase, with an average particle size of 40?nm and a high saturation magnetization of 34?emu g?1. The prepared material was employed as a catalyst for the synthesis of 2-aminotiophene derivatives through the Gewald reaction. This thermally and chemically stable nanocatalyst is environmentally benign, economical and reusable which can be easily recovered using an external magnet. Therefore, it appears that this methodology can be simply extended for industrial purposes.
- Erfaninia,Tayebee,Foletto,Amini,Dusek,Zonoz
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- For FGFR1 tetrahydroben-and thieno [2, 3 - d] amino pyrimidine derivative and its preparation method and application
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The invention relates to tetrahydrobenzothieno[2,3-d]aminopyrimidine derivatives acting on FGFR1, and a preparation method and application thereof. The structure of the tetrahydrobenzothieno[2,3-d]aminopyrimidine derivatives is disclosed as Formula (I). The anti-apoptosis experiment research on the three cells H460 (human lung cancer cell), A549 (human lung adenocarcinoma cell) and U251 (glioma cell) indicates that all the detected compounds have certain inhibition activity, and the inhibition activity increases as the concentration increases. Meanwhile, the FGFR1 kinase inhibition activity experiment indicates that the compounds have certain antitumor activity.
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Paragraph 0044; 0045
(2018/02/22)
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- New thiophene–acridine compounds: Synthesis, antileishmanial activity, DNA binding, chemometric, and molecular docking studies
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In this study, we synthesized eight new compounds containing the 2-amino-cycloalkyl[b]thiophene and acridine moieties (ACT01 and ACS01-ACS07). None tested compounds presented human erythrocyte cytotoxicity. The new compounds presented antipromastigote activity, where ACS01 and ACS02 derivatives presented significant antileishmanial activity, with better performance than the reference drugs (tri and pentavalent antimonials), with respective IC50 values of 9.60?±?3.19 and 10.95?±?3.96?μm. Additionally, these two derivatives were effective against antimony-resistant Leishmania (Leishmania) amazonensis strains. In addition, binding and fragmentation DNA assays were performed. It was observed that the antileishmanial activity of ACS01 is not associated with DNA fragmentation of the promastigote forms. However, it interacted with DNA with a binding constant of 104?m?1. In partial least-squares studies, it was observed that the most active compounds (ACS01 and ACS02) showed lower values of amphiphilic moment descriptor, but there was a correlation between the lipophilicity of the molecules and antileishmanial activity. Furthermore, the docking molecular studies showed interactions between thiophene–acridine derivatives and the active site of pyruvate kinase enzyme with the major contribution of asparagine 152 residue for the interaction with thiophene moiety. Thus, the results suggested that the new thiophene–acridine derivatives are promising molecules as potential drug candidates.
- de Lima Serafim, Vanessa,Félix, Mayara Barbalho,Frade Silva, Daiana Karla,Rodrigues, Klinger Ant?nio da Franca,Andrade, Patrícia Néris,de Almeida, Sinara M?nica Vitalino,de Albuquerque dos Santos, Sanderssonilo,de Oliveira, Jamerson Ferreira,de Lima, Maria do Carmo Alves,Mendon?a-Junior, Francisco Jaime Bezerra,Scotti, Marcus Tullius,de Oliveira, Márcia Rosa,de Moura, Ricardo Olímpio
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p. 1141 - 1155
(2018/03/28)
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- Synthesis and DNase I inhibitory properties of some 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines
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A series of six novel and six known thieno[2,3-d]pyrimidin-4-amines 2–13 were synthesized, and further were used as a starting material for preparation of a small series of eight novel thieno[2,3-d]pyrimidin-4-phthalimides 14–21. Eight compounds, five amine and three phthalimide derivatives, inhibited bovine pancreatic DNase I with an IC50 below 200 μM, being more effective than referent inhibitor crystal violet. Phthalimide derivatives 16, 18 and 19 exhibited higher DNase I inhibitory activity compared to their amine precursors 7, 10 and 11. Compound 19, as the most potent (IC50 = 106 ± 16 μM), offers a good starting point for a design of new DNase I inhibitors. The Pharma RQSAR model showed a significant enhancement of thieno[2,3-d]pyrimidines activity using aryl substituents at R1 position. The E-State RQSAR model clarified the most important structural fragments relevant for DNase I inhibition. Molecular docking and Site Finder module defined the thieno[2,3-d]pyrimidines interactions with the most important catalytic residues of DNase I, including Glu 39, His 134, Asp 168 and His 252. We also found that steric effects and increase of molecular volume play a vital role in DNase I inhibition.
- Ts. Mavrova, Anelia,Dimov, Stefan,Yancheva, Denitsa,Kolarevi?, Ana,Ili?, Budimir S.,Koci?, Gordana,?melcerovi?, Andrija
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p. 693 - 705
(2018/08/02)
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- Design, Synthesis, and Screening of 5-Aryl-3-(2-(pyrrolyl)thiophenyl)-1,2,4-oxadiazoles as Potential Antitumor Molecules on Breast Cancer MCF-7 Cell Line
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The work reported the design and cytotoxic screening of synthetic small molecules: carbonitriles 3a–c, carboximidamides 4a–c, and oxadiazoles 5–19 as antitumor molecules. Molecules 4c, 9, 12, and 14 show promising cytotoxicity profiles against two cell lines higher than prodigiosin (PG). The results of topoisomerase enzyme inhibition assay show that carboximidamide 4c and oxadiazole 14 display potent inhibitory activity in nano-molar concentration higher than PG. In addition, carboximidamide 4c and oxadiazoles 9, 12, and 14 exhibit antiproliferative activities over MCF-7 cells by cell cycle arrest at G1 phase and apoptosis inducing activity by increasing cell population percentages at pre G1 and G2/M phases as shown by DNA-flow cytometry assay and annexin V analysis. Moreover, measurement of p53 and cell death mediators, show that carboximidamide 4c and oxadiazoles 9, 12, and 14 significantly up-regulate p53, Puma and Bax/Bcl-2 ratio levels. Subsequently, pro-apoptotic activities are confirmed by active caspase 3/7 percentages green fluorescence assay.
- Abd el hameid, Mohammed K.
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p. 1181 - 1195
(2018/12/10)
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- Synthesis, Characterization, and Antibacterial and Anti-Inflammatory Activities of New Pyrimidine and Thiophene Derivatives
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Substituted[4,5]thieno[2,3-d]thiazolo[3,2-a]pyrimidin-5-one (3a-b) and pyrimidin-5(6H)-imine (3c-e) were synthesized via reaction of the starting compounds, ethyl 2-amino-substituted[b]thiophene-3-carboxylate (2a-c) and 2-amino-substituted [b]thiophene-3-carbonitrile (2d-f), respectively, with 2-bromothiazole. Synthesis of (bromo-substituted[b]thiophen-2-yl)alkanamide derivatives (4a-e) and thieno[2,3-d][1,3]oxazin-4-imine derivative (5) was accomplished via reaction of the starting compounds with bromoalkyl chloride through nucleophilic substitution; however, for the synthesis of compound 5, nucleophilic substitution was followed by nucleophilic addition to a nitrile group to form the oxazinimine ring. 1-(3-cyano-substituted[b]thiophen-2-yl)-3-(4-(trifluoromethyl)phenyl)thiourea derivatives (6a-c) were obtained via reaction of the starting compounds (2d-f) and 4-(trifluoromethyl phenyl)isothiocyanate. The lead compounds (2d-f) rapidly reacted with 4-(trifluoromethyl)benzaldehyde or 4-(2-pyridyl)benzaldehyde in acidic medium to yield compounds (7a-f) in large quantities. X-ray crystallography of compounds 4c and 7e confirmed their structures. Antimicrobial studies revealed that compound 6a was equally potent to ampicillin against Bacillus strains. Moreover, compounds 3e, 4d, and 6a possessed greater anti-inflammatory potency than that of the standard drug.
- Lahsasni, Siham,Al-Hemyari, Dunya A. M.,Ghabbour, Hazem A.,Mabkhoot, Yahia Nasser,Aleanizy, Fadilah S.,Alothman, Asma A.,Almarhoon, Zainab M.
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- TiO2/nanoclinoptilolite as an efficient nanocatalyst in the synthesis of substituted 2-aminothiophenes
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TiO2/nanoclinoptilolite (TiO2/NCP) was prepared by the mediation of hexadecyltrimethylammonium (HDTMA) as surfactant and used as an effective heterogeneous nanocatalyst for the preparation of substituted 2-aminotiophenes. The modified HDTMA/NCP was impregnated with titanium(IV) chloride solution followed by calcination at 500?°C for 20?h. The obtained nanocomposite was characterized using Fourier transform infrared spectroscopy, field emission scanning electron microscopy, inductively coupled plasma optical emission spectroscopy and X-ray diffraction. Moreover, the prepared nanocomposite had high stability and recoverability under mild and solvent-free conditions.
- Javadi, Farzad,Tayebee, Reza,Bahramian, Bahram
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- A green chemical approach: a straightforward one-pot synthesis of 2-aminothiophene derivatives via Gewald reaction in deep eutectic solvents
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Abstract: The synergic effect of choline chloride/urea as a deep eutectic solvent was investigated in the synthesis of 2-aminothiophene derivatives via a three-component cyclocondensation of a ketone or an aldehyde with activated nitriles and elemental sulfur catalyzed by NaOH as cheap and highly accessible base. The advantages of this catalytic protocol are eco-friendly, easy to set up, reusability, and a simple separation and purification of products without using chromatography in high yields at short times. Graphical abstract: [Figure not available: see fulltext.]
- Shaabani, Ahmad,Hooshmand, Seyyed Emad,Afaridoun, Hadi
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p. 711 - 716
(2017/03/17)
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- Thiophene/thiazole-benzene replacement on guanidine derivatives targeting α2-Adrenoceptors
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Searching for improved antagonists of α2-adrenoceptors, a thorough theoretical study comparing the aromaticity of phenyl-, pyridinyl-, thiophenyl- and thiazolylguanidinium derivatives has been carried out [at M06-2X/6–311++G(p,d) computational level] confirming that thiophene and thiazole will be good ‘ring equivalents’ to benzene in these guanidinium systems. Based on these results, a small but chemically diverse library of guanidine derivatives (15 thiophenes and 2 thiazoles) were synthesised to explore the effect that the bioisosteric change has on affinity and activity at α2-adrenoceptors in comparison with our previously studied phenyl derivatives. All compounds were tested for their α2-adrenoceptor affinity and unsubstituted guanidinothiophenes displayed the strongest affinities in the same range as the phenyl analogues. In the case of cycloakyl systems, thiophenes with 6-membered rings showed the largest affinities, while for the thiazoles the 5-membered analogue presented the strongest affinity. From all the compounds tested for noradrenergic activity, only one compound exhibited agonistic activity, while two compounds showed very promising antagonism of α2-adrenoceptors.
- Flood, Aoife,Trujillo, Cristina,Sanchez-Sanz, Goar,Kelly, Brendan,Muguruza, Carolina,Callado, Luis F.,Rozas, Isabel
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supporting information
p. 38 - 50
(2017/06/23)
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- Exploring the scope of the Gewald reaction: Expansion to a four-component process
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An efficient four-component reaction was developed to take advantage of the reactivity of the 2-aminothiophene-3-carbonitrile functionality, which is obtained during the classical three-component Gewald reaction. Various α-methylene bearing ketones were reacted with malononitrile, elemental sulfur, and aryl/heteroarylnitrile derivatives in t-BuOH/NaOH to afford 2-arylthieno[2,3-d]pyrimidin-4-amines in high yields. Preliminary studies revealed the photophysical properties of the products and their potential for use as metal sensors.
- Abaee, M. Saeed,Hadizadeh, Atefeh,Mojtahedi, Mohammad M.,Halvagar, Mohammad R.
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supporting information
p. 1408 - 1412
(2017/03/16)
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- Synthesis of novel heterocyclic compounds incorporate 4,5,6,7-tetrahydrobenzo[b]thiophene together with their cytotoxic evaluations
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The 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene was the key starting compound used to synthesize new thiazole, pyrimidine, pyran, pyridine and thiazine derivatives. The cytotoxicity of the synthesized compounds was studied towards the three cancer cell lines namely MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer) and SF-268 (central nervous system (CNS) cancer) in addition to the normal cell line (WI-38) using doxorubicin as the reference drug. The study showed that compounds 5, 9a, 15b, 17c, 18 and 21b were the most potent compounds.
- Abdallah, Amira Elsayed Mahmoud,Mohareb, Rafat Milad,Khalil, Eid Metwally,Elshamy, Menna Alla Mohamed Abd Elaleem
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p. 469 - 477
(2017/05/17)
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- Synthesis, Antibacterial Activity, and Docking Studies of 1,2,3-triazole-tagged Thieno[2,3-d]pyrimidinone Derivatives
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Novel (1-(substituted phenyl)-1H-1,2,3-triazol-4-yl)methyl-2-(4-oxo-5,6,7,8-tetrahydrobenzo[1,2]thieno[2,3-d]pyrimidin-3(4H)-yl)acetate derivatives were synthesized. All the compounds showed significant antibacterial activity against Gram-negative (Escherichia coli and Klebsiella pneumonia) and Gram-positive (Bacillus subtilis and Bacillus cereus) bacteria. Particularly, (1-(3-nitrophenyl)-1H-1,2,3-triazol-4-yl)methyl-2-(4-oxo-5,6,7,8-tetrahydrobenzo[1, 2]thieno[2,3-d]pyrimidin-3(4H)-yl)acetate was found to be most potent against E.?coli, K.?pneumonia, and B.?subtilis with MIC 25?μg/ml. Molecular docking was also performed on purine riboswitch of B.?subtilis and thiamine pyrophosphate riboswitch of E.?coli.
- Aruna Kumari,Triloknadh,Harikrishna,Vijjulatha,Venkata Rao
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p. 3672 - 3681
(2017/11/21)
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- Design and Synthesis of 4-Anilinothieno[2,3-d]pyrimidine-Based Compounds as Dual EGFR/HER-2 Inhibitors
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Dual inhibition of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER-2) is an attractive cancer therapeutic approach. In this study, new series of 4-anilinothieno[2,3-d]pyrimidines were designed, synthesized, and tested as dual EGFR/HER-2 kinase inhibitors. Five compounds (8a, 8b, 8e–g) demonstrated low to submicromolar inhibition of both kinases with IC50 values of 1.2, 0.6, 0.3, 0.2, 0.4 μM and 8.2, 3.4, 1.3, 0.5, 2.7 μM for the EGFR and HER-2, respectively. Introduction of a 5,6-tetramethylene moiety into the thienopyrimidine core bearing a 4-(3-fluorobenzyloxy)-3-chloroaniline tail resulted in a favorable increase in both the EGFR and HER-2 inhibitory activities. Compound 8f (IC50 EGFR/HER-2: 0.2/0.5 μM) also exhibited significant cell growth inhibition on some specific NCI cell lines, especially ovarian, breast, non-small-cell lung cancer, and renal cancer cell lines.
- Abd El Hadi, Soha R.,Lasheen, Deena S.,Hassan, Mahmoud A.,Abouzid, Khaled A. M.
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p. 827 - 847
(2016/11/09)
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- Synthesis and Evaluation of Biological and Antitumor Activities of Tetrahydrobenzothieno[2,3-d]Pyrimidine Derivatives as Novel Inhibitors of FGFR1
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A series of tetrahydrobenzothieno[2,3-d]pyrimidine derivatives were designed, synthesized, and evaluated as inhibitors of FGFR1. These analogs were synthesized via Gewald's reaction under mild conditions. The structures of the synthesized compounds were characterized by spectroscopic data (IR, 1H NMR and MS). Their antitumor activities were evaluated against H460, A549 and U251 cell lines in vitro. Results revealed that the tested compounds showed moderate antitumor activities. Structure-activity relationship analyses indicated that compounds with an aromatic ring substituted in the C-2 position or with larger molecules such as 3g, 4c, and 7 were more effective than others. The compound, 3g (78.8% FGFR1 inhibition at 10 μm), was identified to have the most potent antitumor activities, with IC50 values of 7.7, 18.9, and 13.3 μm against the H460, A549, and U251 cell lines, respectively. Together, the results suggested that tetrahydrobenzothieno[2,3-d]pyrimidine derivatives may serve as a potential agent for the treatment of FGFR1-mediated cancers.
- Wang, Xuebao,Chen, Di,Yu, Shufang,Zhang, Zaikui,Wang, Yu,Qi, Xiaolu,Fu, Weitao,Xie, Zixin,Ye, Faqing
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p. 499 - 507
(2016/03/19)
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- An innovative synthesis of tertiary hydroxyl thieno[2,3-d]pyrimidinone skeleton: Natural-like product from the tandem reaction of o-aminothienonitrile and carbonyl compound
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A straightforward base accelerant tandem protocol for the synthesis of the tertiary hydroxyl natural-like thieno[2,3-d]pyrimidinone skeleton was developed from the cyclocondensation of o-aminothienonitrile and carbonyl compound. The reaction process includes PDF conversion and photo-catalytic oxygenation. This synthetic strategy offers an alternative method for regioselective construction of tertiary hydroxylated thieno[2,3-d]pyrimidinone architectures with kinetic, thermodynamic control, and six-member ring effect.
- Yang, Junjuan,Shi, Daxin,Hao, Pengfei,Yang, Deli,Zhang, Qi,Li, Jiarong
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supporting information
p. 2455 - 2461
(2016/05/19)
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- Antileishmanial activity of new thiophene–indole hybrids: Design, synthesis, biological and cytotoxic evaluation, and chemometric studies
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In the present work, thirty-two hybrid compounds containing cycloalka[b]thiophene and indole moieties (TN5, TN5 1–7, TN6, TN6 1–7, TN7, TN7 1–7, TN8, TN8 1–7) were designed, synthesized and evaluated for their cytotoxic and antileishmanial activity against Leishmania amazonensis promastigotes. More than half of the compounds (18 compounds) exhibited significant antileishmanial activity (IC50lower than 10.0 μg/L), showing better performance than the reference drugs (tri- and penta-valent antimonials). The most active compounds were TN8-7, TN6-1 and TN7 with respective IC50values of 2.1, 2.3 and 3.2 μg/mL. Demonstrating that all of the compounds were less toxic than the reference drugs, even at the highest evaluated concentration (400 μg/mL), no compound tested presented human erythrocyte cytotoxicity. Compound TN8-7's effectiveness against a trivalent antimony-resistant culture was demonstrated. It was observed that TN8-7's antileishmanial activity is associated with DNA fragmentation of L. amazonensis promastigotes. Chemometric studies (CPCA, PCA, and PLS) highlight intrinsic solubility/lipophilicity, and compound size and shape as closely related to activity. Our results suggest that hybrid cycloalka[b]thiophene–indole derivatives may be considered as lead compounds for further development of new drugs for the treatment of leishmaniasis.
- Félix, Mayara B.,de Souza, Edson R.,de Lima, Maria do C.A.,Frade, Daiana Karla G.,Serafim, Vanessa de L.,Rodrigues, Klinger Antonio da F.,Néris, Patrícia Lima do N.,Ribeiro, Frederico F.,Scotti, Luciana,Scotti, Marcus T.,de Aquino, Thiago M.,Mendon?a Junior, Francisco Jaime B.,de Oliveira, Márcia R.
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p. 3972 - 3977
(2016/08/24)
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- Spiro- and substituted tetrahydrobenzo[b]thiophene-triazaphospholes and phosphoramidates as potent antineoplastic agents: Synthesis, biological evaluation, and SAR studies
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New and efficient conjugate addition reaction of trimethyl, triethyl, and triisopropyl phosphites with 2-azido-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile was developed and furnished spiro-triazaphosphole-oxide derivatives in ≈70 % yield. Contrary to these results, linear substituted phosphoramidates were obtained from the reaction of the azide with dimethyl, diethyl, and diisopropyl phosphites. N-Alkylamino- or 2-aminotetrahydrobenzo[b]thiophene-3-carbonitrile was also isolated in ~10 % yield from the previous two reactions. In the context of this work, hexaalkylphosphorus triamides were caused to react with the same substrate afforded the corresponding phosphoric triamides only in the presence of a protonating agent (dil. alcohol). The three reactions proceeded smoothly, cleanly, and were completed within ~6 h at r.t. Pharmacological evaluation results of antibreast, anticolon, and antiprostate carcinoma cell lines properties for the products were discussed in terms of structure-activity relationship to define a chromophore for lead compounds.
- Abdou, Wafaa M.,Ganoub, Neven A.,Sabry, Eman
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p. 619 - 626
(2016/03/19)
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- Basic Ionic Liquid [bmIm]OH-Mediated Gewald Reaction as Green Protocol for the Synthesis of 2-Aminothiophenes
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A simple, efficient, and environmental friendly procedure was developed based on the Gewald reaction for the synthesis of 2-aminothiophenes using a basic ionic liquid [bmIm]OH as both catalyst and solvent. Besides being a green protocol, the method offers advantages of successful synthesis of a variety of alkyl, aryl, alkoxy, and alkylamino-2-aminothiophenes in good yields.
- Kaki, Venkata Rao,Akkinepalli, Raghuram Rao,Deb, Pran Kishore,Pichika, Mallikarjuna Rao
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p. 119 - 126
(2015/10/20)
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- Novel thiazole-thiophene conjugates as adenosine receptor antagonists: Synthesis, biological evaluation and docking studies
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Here we report novel thiazole-thiophene conjugates as adenosine receptor antagonists. All the molecules were evaluated for their binding affinity for adenosine receptors. Most of the molecules were found to interact with the A1, A2A and A3 adenosine receptor subtypes with good affinity values. The most potent and selective compound 8n showed an A3 Ki value of 0.33 μM with selectivity ratios of >90 versus the A1 and >30 versus the A2 subtypes. For compound 8n docking studies into the binding site of the A3 adenosine receptor are provided to visualize its binding mode.
- Pandya, Dhaivat H.,Sharma, Jayesh A.,Jalani, Hitesh B.,Pandya, Amit N.,Sudarsanam,Kachler, Sonja,Klotz, Karl Norbert,Vasu, Kamala K.
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p. 1306 - 1309
(2015/03/14)
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- 2-Amino-thiophene derivatives present antileishmanial activity mediated by apoptosis and immunomodulation in vitro
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This study evaluated the effects of 2-amino-thiophene derivatives on the promastigote and amastigote forms of Leishmania (Leishmania) amazonensis and their possible mechanisms of action. Initially, we evaluated the antileishmanial activity of ten 2-amino-thiophene derivatives on promastigote and axenic amastigote forms of Leishmania amazonensis and their cytotoxicity against murine macrophages and human red blood cells. Three promising compounds were selected for studies of the cell death process using flow cytometry analysis and a DNA fragmentation assay. The effects of the compounds were assessed on intramacrophagic amastigotes, and the modulation of cytokine and NO production was investigated. All thiophene derivatives showed antileishmanial activity against promastigotes and axenic amastigotes with less toxicity for murine macrophages and human red blood cells. The best values were obtained for compounds containing a lateral indole ring. Docking studies suggested that these compounds played an important role in inhibiting trypanothione reductase (TryR) activity. The selected compounds SB-200, SB-44, and SB-83 induced apoptosis in promastigotes involving phosphatidylserine externalization and DNA fragmentation in a pattern similar to that observed for the positive control. Additionally, SB-200, SB-44, and SB-83 significantly reduced the infection index of macrophages by the parasites; for compounds SB-200 and SB-83 this reduction was associated with increased TNF-α, IL-12, and NO levels. This study demonstrated the effective and selective action of 2-amino-thiophene derivatives against L. amazonensis, resulting in apoptosis-like cell death and immunomodulation in vitro. The results suggest that they are promising compounds for the development of new leishmanicidal drugs.
- Rodrigues, Klinger Antonio Da Franca,Dias, Cinthia Nobrega De Sousa,Neris, Patricia Lima Do Nascimento,Rocha, Juliana Da Camara,Scotti, Marcus Tullius,Scotti, Luciana,Mascarenhas, Sandra Rodrigues,Veras, Robson Cavalcante,Medeiros, Isac Almeida De,Keesen, Tatjana De Souza Lima,Oliveira, Tiago Bento De,Lima, Maria Do Carmo Alves De,Balliano, Tatiane Luciano,Aquino, Thiago Mendonc? De,Moura, Ricardo Olimpio De,Mendonc? Junior, Francisco Jaime Bezerra,Oliveira, Marcia Rosa De
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- Facile synthesis of novel N4-substituted 2-(trifluoromethyl)-tetrahydrobenzothieno[2,3-d]pyrimidine derivatives
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A series of novel N4-substituted 2-(trifluoromethyl)-tetrahydrobenzothieno[2,3-d]pyrimidine derivatives were synthesized by a facile three-step procedure that presented such advantages as easily accessible starting materials, mild reaction conditions, simple protocol and good overall yields. The structures of the title compounds were confirmed by IR, 1H NMR, 13C NMR, EI-MS, elemental analysis, and single-crystal X-ray diffraction.
- Wang, Fasong,Gao, Hui,Yang, Ping,Wang, Yan,Song, Xinjian
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p. 700 - 705
(2015/04/14)
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- A convenient synthesis of new 2-cyanomethylthieno[3,2-e]1[1,2,4]- triazolo[1,5-c]pyrimidine derivatives
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A new series of 2-cyanomethylthienotriazolopyrimidines has been synthesized in good yield through a facile method using substituted aminothiophene-3- carbonitrile as building block and cyanoacetic acid hydrazide as reagent in one framework. The structure of the synthesized compounds was established on the basis of their mass and spectral data.
- Jabli, Dhiab,Dridi, Khaireddine,El Efrit, Mohamed L.
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p. 403 - 408
(2014/05/20)
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- Efficient three-component Gewald reactions under Et3N/H 2O conditions
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In a medium consisting of triethylamine and water, methylene ketones undergo room temperature Gewald reactions with elemental sulfur and ethyl cyanoacetate (or malononitrile) to yield 2 aminothiophene derivatives efficiently within short time periods. Because of the high polarity of the medium, products precipitate in the reaction mixtures spontaneously. This makes isolation of the products easy by simple filtration and avoids cumbersome chromatographic separations. Mechanistic studies suggest that the reactions proceed via a Knoevenagel condensation pathway(equation presented). 2013
- Abaee, M. Saeed,Cheraghi, Somayeh
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p. 261 - 269
(2014/04/03)
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- Solvent-free synthesis of 2-aminothiophene-3-carbonitrile derivatives using high-speed vibration milling
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The solvent-free synthesis of 2-aminothiophene-3-carbonitrile derivatives by high-speed vibration milling using the inexpensive and environmentally friendly Et2NH as a catalyst was studied. The reaction conditions were optimised and the derivatives were obtained in good yield. This method has advantages in terms of short reaction time and facile conditions.
- Xu, Fang,Li, Yujin,Xu, Fengshuang,Ye, Qing,Han, Liang,Gao, Jianrong,Yu, Wubin
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p. 450 - 452
(2014/08/05)
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- Aqueous DABCO, an efficient medium for rapid organocatalyzed Knoevenagel condensation and the Gewald reaction
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In the presence of water and 1,4-diazabicyclo[2.2.2]octane, several aldehydes and cyclic ketones underwent efficient Knoevenagel condensation with malononitrile and ethyl cyanoacetate to produce the respective α.β-unsaturated systems within fairly short time periods. As a result, high yields of conjugated products were easily obtained. Products could be engaged in a Gewald reaction, either stepwise or in situ, to produce efficiently their respective 2-aminothiophenes within 4-7 h. TUeBITAK.
- Abaee, Mohammad Saeed,Cheraghi, Somayeh
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p. 650 - 660
(2014/07/07)
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- Bovine serum albumin-catalyzed one-pot synthesis of 2-aminothiophenes via Gewald reaction
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A novel bovine serum albumin (BSA)-catalyzed Gewald reaction in one-pot was developed in this work. The influence of reaction conditions including solvent, temperature and catalyst loading was investigated, and 12 multi-substituted 2-aminothiophene derivatives were prepared with moderate to excellent yields. Recycle experiments were designed to demonstrate the reusability of BSA. This novel activity of BSA to catalyze Gewald reaction is of practical significance in expanding the application of biocatalysts.
- Zhao, Dan-Dan,Li, Li,Xu, Fan,Wu, Qi,Lin, Xian-Fu
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- KG-60-piperazine as a new heterogeneous catalyst for gewald three-component reaction
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Piperazine supported on amorphous silica (KG-60-piperazine) as a basic catalyst acts in the Gewald three-component reaction of some aldehydes and ketones with malononitrile as well as ethyl cyanoacetate. The catalyst shows general utility with a variety of starting carbonyl compounds. Moreover, the catalyst can be reused for four additional cycles without significant loss of the activity. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.
- Rezaei-Seresht, Esmail,Tayebee, Reza,Yasemi, Mohammad
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p. 1859 - 1864
(2013/05/21)
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- First Gewald reaction ignited by sodium polysulfide: Greener ultrasound-promoted synthesis of substituted 2-aminothiophenes in the absence of catalyst
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In this paper, a modified and facile Gewald reaction triggered by sodium polysulfide in the absence of catalytic base was developed. This approach involves a one-pot ultrasound-irritated aqueous reaction between ketones or aldehydes, malononitrile, and sodium polysulfide, which are converted into the corresponding 2-aminothiophene derivatives in moderate to high yields. In comparison with conventional methods, the prominent features of this sonocatalyzed procedure are experimental simplicity, good functional group tolerance, atom efficiency, and the use of water as a green solvent.
- Liang, Chengyuan,Lei, Dong,Wang, Xiuzhen,Zhang, Qingqing,Yao, Qizheng
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p. 458 - 463
(2013/10/21)
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