- 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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- Evaluation of the dyeing performance and antimicrobial activity of dyed wool fabric with New Azo Dyes
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A series of novel mono and diazothienopyrazolone dyes were successfully synthesized and characterized, the coloration performance of the prepared dyes was assessed on wool fabrics. The structures of the synthesized dyes were characterized and confirmed by
- El-Hady, Rafat,Regal, Mohsen K.A.,Kafafy, Hany,Abd El-Sattar, Nour E.A.
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p. 5291 - 5306
(2021/09/03)
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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.
- Xie, Hong-Xu,Zhang, Juan,Li, Yue,Zhang, Jin-He,Liu, Shan-Kui,Zhang, Jie,Zheng, Hua,Hao, Gui-Zhou,Zhu, Kong-Kai,Jiang, Cheng-Shi
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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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- 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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- 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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- 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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- 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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- 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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- 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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- 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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- Structure–activity relationships for inhibitors of Pseudomonas aeruginosa exoenzyme S ADP-ribosyltransferase activity
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During infection, the Gram-negative opportunistic pathogen Pseudomonas aeruginosa employs its type III secretion system to translocate the toxin exoenzyme S (ExoS) into the eukaryotic host cell cytoplasm. ExoS is an essential in vivo virulence factor that enables P. aeruginosa to avoid phagocytosis and eventually kill the host cell. ExoS elicits its pathogenicity mainly via ADP-ribosyltransferase (ADPRT) activity. We recently identified a new class of ExoS ADPRT inhibitors with in vitro IC50 of around 20 μM in an enzymatic assay using a recombinant ExoS ADPRT domain. Herein, we report structure–activity relationships of this compound class by comparing a total of 51 compounds based on a thieno [2,3-d]pyrimidin-4(3H)-one and 4-oxo-3,4-dihydroquinazoline scaffolds. Improved inhibitors with in vitro IC50 values of 6 μM were identified. Importantly, we demonstrated that the most potent inhibitors block ADPRT activity of native full-length ExoS secreted by viable P. aeruginosa with an IC50 value of 1.3 μM in an enzymatic assay. This compound class holds promise as starting point for development of novel antibacterial agents.
- Saleeb, Michael,Sundin, Charlotta,Aglar, ?znur,Pinto, Ana Filipa,Ebrahimi, Mahsa,Forsberg, ?ke,Schüler, Herwig,Elofsson, Mikael
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supporting information
p. 568 - 576
(2017/12/07)
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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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- 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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- 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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- 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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- 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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- 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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- 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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- 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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- 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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- Facile synthesis and antitumor activity of novel 2-trifluoromethylthieno[2, 3-d]pyrimidine derivatives
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A series of novel 2-trifluoromethylthieno[2,3-d]pyrimidine derivatives were synthesized by a facile three-step procedure that afforded advantages of mild reaction conditions, simple protocol and good yields. The structures of the final compounds were confirmed by IR, NMR, EI-MS, elemental analysis, and X-ray diffraction. Preliminary bioassay results showed that some of the analogs exhibit excellent antitumor activity against MCF-7 and HepG2, especially compounds 3a, 3b, 3e and 3h exhibited higher activity than the positive control gefitinib.
- Song, Xin-Jian,Yang, Ping,Gao, Hui,Wang, Yan,Dong, Xing-Gao,Tan, Xiao-Hong
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p. 1006 - 1010
(2014/08/18)
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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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- 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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- 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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- Easy single-step preparation of ZnO nano-particles by sedimentation method and studying their catalytic performance in the synthesis of 2-aminothiophenes via Gewald reaction
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Zinc oxide is a multi-purpose active material with important catalytic applications. In this study, nano-sized ZnO particles were easily synthesized through sedimentation of zinc acetate di-hydrate in absolute ethanol and were characterized by XRD and SEM. The XRD results indicated pure wurtzite structure with the average particle size of 26.9 nm for the nano-particles. It was observed that size of ZnO nano-particles was decreased while solution concentration was increased. This observation would be explained considering enhancing nucleation processes of nano-particles at high concentration of zinc acetate. The prepared nano-particles (2.5 mol%) were used as catalyst for the fast and efficient synthesis of 2-aminothiophenes under solvent free conditions. The three-component mixture of a carbonyl compound, malonodinitrile, and elemental sulfur was converted into the corresponding 2-aminothiophene in moderate to high yields with excellent selectivity.
- Tayebee, Reza,Javadi, Farzad,Argi, Gholamreza
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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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- An efficient one-pot synthesis of substituted 2-aminothiophenes via three-component gewald reaction catalyzed by l -proline
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An efficient one-pot procedure for the direct catalytic synthesis of substituted 2-aminothiophenes catalyzed by l-proline under mild reaction conditions has been developed. A variety of functionalized 2-aminothiophene scaffolds were assembled in high yields by this catalytic protocol. Low catalyst loading, simple procedure, and high yields are the important attributes of this methodology.
- Wang, Tao,Huang, Xian-Gui,Liu, Jia,Li, Bo,Wu, Jin-Jin,Chen, Kai-Xian,Zhu, Wei-Liang,Xu, Xiao-Yong,Zeng, Bu-Bing
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experimental part
p. 1351 - 1354
(2010/08/20)
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- Design, synthesis, and molecular-modeling study of aminothienopyridine analogues of tacrine for Alzheimer's disease
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2-Amino-3-cyanothiophenes were successfully condensed with a number of cycloalkanones to afford tacrine analogues in a one-step reaction mediated with Lewis acid. The newly synthesized compounds have been tested for their ability to inhibit acetylcholine esterase (AChE) activity using tacrine as standard drug. Some of the tested compounds showed moderate inhibitory activity in comparison with tacrine, especially compounds 6a which displayed the highest inhibitory activity. Furthermore, molecular-modeling studies were performed in order to rationalize the obtained biological results.
- Badran, Mohga M.,Hakeem, Maha Abdel,Abuel-Maaty, Suzan M.,El-Malah, Afaf,Salam, Rania M. Abdel
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scheme or table
p. 590 - 601
(2011/06/26)
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- Activation of elemental sulfur by electrogenerated cyanomethyl anion: Synthesis of substituted 2-aminothiophenes by the Gewald reaction
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The activation of elemental sulfur (S8) has been achieved by means of electrogenerated cyanomethyl anion [easily obtained by galvanostatic reduction from acetonitrile/tetraethylammonium hexafluorophosphate (MeCN-Et 4NPF4)]. The activated sulfur reacted with ylidenemalononitriles to give substituted 2-aminothiophenes in very high yields. This variation of the Gewald reaction has been carried out using only catalytic amounts of electricity and supporting electrolyte. A proposed mechanism for the interaction between S8 and cyanomethyl anion is described.
- Feroci, Marta,Chiarotto, Isabella,Rossi, Leucio,Inesi, Achille
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supporting information; experimental part
p. 2740 - 2746
(2009/10/06)
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- Microwave accelerated Gewald reaction: synthesis of 2-aminothiophenes
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Microwave-promoted synthesis of 2-aminothiophenes by multicomponent reactions of a ketone with an active nitrile and elemental sulfur under KF-alumina catalysis is described.
- Sridhar, Madabhushi,Rao, Rayankula Mallikarjuna,Baba, Nanduri H.K.,Kumbhare, Ravindra M.
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p. 3171 - 3172
(2007/10/03)
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- THIENO-PYRIDINE DERIVATIVES AS GABA-B ALLOSTERIC ENHANCERS
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The present invention relates to compounds of formula (I), Wherein R1 to R5 are as defined in the specification which compounds are active on the GABABreceptor and can be used for the manufacture of medicaments useful for treating CNS disorders.
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Page/Page column 42
(2008/06/13)
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- Novel substituted 3-cyanothiophene acetamides as glucagon receptor antagonists
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The present invention relates to compounds of formula (I) wherein R1, R2, R3, R4 and n are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The compounds are useful for the treatment and/or prophylaxis of diseases which are associated with the antagonism of the glucagon receptor, such as diabetes.
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Page/Page column 9
(2008/06/13)
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- Calcined Mg-Al hydrotalcite as a heterogeneous base catalyst for gewald aminothiophene synthesis
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Calcined Mg-Al hydrotalcite (Mg/Al=4) has been conveniently employed as a heterogeneous base catalyst in the synthesis of 2-amino-3-cyanothiophenes adopting a one pot Gewald aminothiophene methodology.
- Rajagopal,Jyothi,Daniel,Srinivasan,Rao
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p. 3113 - 3117
(2007/10/03)
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- Synthesis of some biologically active agents derived from thieno [2,3-d]pyrimidine derivatives
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The key compound 1-amino-8-iminocyclopenta[b]thieno[2,3-d]pyrimidine (5g) was prepared by reaction of 2-amino-3-cyano cyclopenta[b]thiophene (1) with triethyl orthoformate followed by cyclization with hydrazine hydrate in ethanol. Refluxing of 1 with triethyl orthoformate in the presence of acetic anhydride gave an unexpected product 2, while reaction with aromatic amines gave the condensation products 4a-c. Reaction of 5g with formic acid, other formate derivatives, ethoxymethylenemalononitrile and ethyl ethoxymethylenecyanoacetate gave the same product cyclopentathieno[2,3-d]pyrimidine]-1,2,4-triazolo[3,2-f]pyrimidine 6. Compound 7 was prepared by different methods. Treatment of 5g with dicarbonyl compounds gave the triazol derivatives 8-11. Reaction of 5g with phenyl isothiocyanate, carbon disulphide and ethyl chloroformate gave the corresponding derivatives 12-14, respectively. Condensation of 5g with some selected aromatic and heterocyclic aldehydes, acetone, N-acetyl isatin and isatin gave the condensation products 15a-e, 16-18, respectively in good yields. Many of the synthesized compounds were tested in vitro for their inhibitory activity against a variety of bacteria such as: Serratia rhodnii, Bacillus cereus, Staphylococcus citreus and Pseudomonas aeruginosa and fungi such as: Aspergillus flavus, Penicillium chrysogenum and Alternaria alternata. Some compounds showed modest activity.
- Hozien, Zeinab A.,Abdel-Wahab,Hassan,Atta,Ahmed
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p. 753 - 758
(2007/10/03)
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