- Microwave assisted synthesis of some novel thiadiazolothienopyrimidines
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3-Amino-2-mercapto-3,5,6,7,8,9-hexahydro-4H-cyclohepta[4,5]thieno[2,3-d] pyrimidin-4-one (4) was prepared, and from this a series of 2-(arylaminomethyl)- 7,8,9,10-tetrahydro-6H,11H-cyclohepta[4,5]thieno[2,3-d][1,3,4]thiadiazolo [3,2-a]pyrimidin-11-ones (6
- Raghu Prasad,Raziya,Pran Kishore
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Read Online
- Synthesis and biological activity of new cycloalkylthiophene-Schiff bases and their Cr(III) and Zn(II) complexes
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A series of some novel Ethyl 2-((1-hydroxynaphthalen-2-yl)methyleneamino)- 5,6-dihydro-4H-cyclopenta[b]thiopehene-3-carboxylate, Ethyl 2-((1- hydroxynaphthalen- 2-yl)methyleneamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylate, Ethyl 2-((1-hydroxynaphtalen-2-yl)methyleneamino)-5,6,7,8- tetrahydro-4H-cyclohepta [b]thiophene-3-carboxylate and their Cr(III) and Zn(II) complexes have been synthesized. All of these substances have been examined for antibacterial activity against pathogenic strains Listeria monocytogenes 4b (ATCC-19115), Staphylococcus aureus (ATCC25923), Proteus OX2 Wrah (ETS.40-A-4), Escherichia coli (ATCC-1280), Salmonella typhi H (NCTC-901.8394), Pseudomonas putida sp., Brucella abortus (A.99, UK-1995) RSKK-03026. Sh. boydii type 11 (Pasteur51.6), Sh. boydii type 16 (cHe 67.11), Sh. boydii type 6 (RSKK-96043), and antifungal activity against Candida albicans (Y-1200-NIH, Tokyo). Some of the compounds exhibited activity comparable to ampicillin ofloxacin, nystatin, kanamycin, sulphamethoxazol, amoxycillin, and chloroamphenicol. Most of the studied compounds were found effective against bacteria studied and yeast. Birkha?user Boston 2009.
- Altundas, Aliye,Sar?, Nurs?en,Colak, Naki,?gütcü, Hatice
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Read Online
- Design, Synthesis, and Structure-Activity Relationship of N-Aryl- N′-(thiophen-2-yl)thiourea Derivatives as Novel and Specific Human TLR1/2 Agonists for Potential Cancer Immunotherapy
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The previous virtual screening of ten million compounds yielded two novel nonlipopeptide-like chemotypes as TLR2 agonists. Herein, we present the chemical optimization of our initial hit, 1-phenyl-3-(thiophen-2-yl)urea, which resulted in the identification of SMU-C80 (EC50 = 31.02 ± 1.01 nM) as a TLR2-specific agonist with a 370-fold improvement in bioactivity. Mechanistic studies revealed that SMU-C80, through TLR1/2, recruits the adaptor protein MyD88 and triggers the NF-κB pathway to release cytokines such as TNF-α and IL-1β from human, but not murine, cells. To the best of our knowledge, it is the first species-specific TLR1/2 agonist reported until now. Moreover, SMU-C80 increased the percentage of T, B, and NK cells ex vivo and activated the immune cells, which suppressed cancer cell growth in vitro. In summary, we obtained a highly efficient and specific human TLR1/2 agonist that acts through the MyD88 and NF-κB pathway, facilitating cytokine release and the simultaneous activation of immune cells that in turn affects the apoptosis of cancer cells.
- Chen, Zhipeng,Zhang, Lina,Yang, Junjie,Zheng, Lu,Hu, Fanjie,Duan, Siqin,Nandakumar, Kutty Selva,Liu, Shuwen,Yin, Hang,Cheng, Kui
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supporting information
p. 7371 - 7389
(2021/06/28)
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- PYRIDINESULFONAMIDE DERIVATIVES AS TRAP1 MODULATORS AND USES THEREOF
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The present disclosure provides compounds of Formula (I): and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrugs thereof. The provided compounds may be tumor necrosis factor ("TNF") receptor associated protein 1 ("TRAP1") modulators (e.g., TRAP1 activators). The provided compounds may also rescue the activity in PTEN-induced kinase 1 ("PINK1") loss of function contexts. The provided compounds may also improve mitochondrial health, function, quality, quantity, and/or activity, and/or reduce the production of reactive oxygen species. The provided compounds may also refold or solubilize aggregated or misfolded proteins such as a-synuclein. The present disclosure also provides pharmaceutical compositions comprising the provided compounds; kits comprising the provided compounds or pharmaceutical compositions; and methods of using the provided compounds and pharmaceutical compositions (e.g., for treating a disease in a subject in need thereof).
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Paragraph 00288; 00623-00624
(2021/09/26)
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- Synthesis and characterization of 1,2,4-triazolo[1,5-a]pyrimidine-2-carboxamide-based compounds targeting the PA-PB1 interface of influenza A virus polymerase
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Influenza viruses (Flu) are responsible for seasonal epidemics causing high rates of morbidity, which can dramatically increase during severe pandemic outbreaks. Antiviral drugs are an indispensable weapon to treat infected people and reduce the impact on
- Massari, Serena,Bertagnin, Chiara,Pismataro, Maria Chiara,Donnadio, Anna,Nannetti, Giulio,Felicetti, Tommaso,Di Bona, Stefano,Nizi, Maria Giulia,Tensi, Leonardo,Manfroni, Giuseppe,Loza, Maria Isabel,Sabatini, Stefano,Cecchetti, Violetta,Brea, Jose,Goracci, Laura,Loregian, Arianna,Tabarrini, Oriana
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- Straightforward synthesis, characterization, and cytotoxicity evaluation of hybrids of natural alkaloid evodiamine/rutaecarpine and thieno[2,3-d]pyrimidinones
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Dozens of hybrids of natural alkaloid evodiamine/rutaecarpine and thieno[2,3-d]pyrimidinones were synthesized in a straightforward method by condensation of substituted 2H-thieno[2,3-d][1, 3]oxazine-2,4(1H)-diones or N-methyl-2H-thieno[2,3-d][1, 3]oxazine-2,4(1H)-dione with 3,4-dihydro-β-carbolines. In vitro cytotoxic assay discovered that compounds 9a, 10e, 11a, 11d, 11f, and 12a could induce antiproliferation against four different types of human cancer cells while compounds 10f and 12e were inactive. Notably, compound 11a displayed potent cell cytotoxicity for human non-small cell lung cancer cells A549, PC-9, human prostate cancer cells PC-3, and human breast cancer cell line MCF-7. Furthermore, compound 11a exhibited strong colony formation inhibition to A549 cells. These results unfold potential anticancer therapeutic applications of hybrids of thieno[2,3-d]pyrimidinones and quinazolinones.
- Aisa, Haji Akber,Cao, Jian-Guo,Huang, Guo-Zheng,Liu, Fei-Ze,Nie, Li-Fei,Wang, Si-Si,Xiamuxi, Hainimu
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- Synthesis and Evaluation of 2-Aminothiophene Derivatives as Staphylococcus aureus Efflux Pump Inhibitors
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2-aminothiophene derivatives (2AT) in which the thiophene ring is fused with a cycloalkyl or a N-acylated piperidine ring by positions 5 and 6 and carrying a 3-carbethoxy group were synthesized and their bacterial growth and enzyme inhibitory effects against efflux proteins of Staphylococcus aureus leading to resistance to fluoroquinolones and erythromycin (ERY) were investigated. Compounds that most effectively decreases the minimum inhibitory concentrations (MICs) of ciprofloxacin (CIP) were assayed for their dose and time effects on the accumulation and efflux of ethidium bromide (EtBr) in the SA-1 strain. None of the compounds displayed antibacterial activity however, three derivatives carrying 2-amino, 2-aminoacetyl and 2-aminotrifluoroacetyl group enhanced the activity of CIP and ERY by 8- and 16-fold, respectively, and were able to restore the sensitivity of resistant strains, acting as typical efflux pump inhibitors (EPIs). The 2-aminoacetyl and 2-aminotrifluoroacetyl derivatives and two other piperidinyl 2-aminotrifluoroacetyl derivatives increased EtBr accumulation in a dose- and time-dependent manner, and one of them was also able to inhibit the EtBr efflux. Taken together, these results represent an important advance in the development of new EPIs, and demonstrate that 2AT represent a good scaffold for developing new antibiotic adjuvants.
- da Cruz, Rayssa M. D.,Zelli, Renaud,Benshain, Sarah,da Cruz, Ryldene M. D.,Siqueira-Júnior, José P.,Décout, Jean-Luc,Mingeot-Leclercq, Marie-Paule,Mendon?a-Junior, Francisco J. B.
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p. 716 - 725
(2020/04/09)
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- From cycloheptathiophene-3-carboxamide to oxazinone-based derivatives as allosteric HIV-1 ribonuclease H inhibitors
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The paper focussed on a step-by-step structural modification of a cycloheptathiophene-3-carboxamide derivative recently identified by us as reverse transcriptase (RT)-associated ribonuclease H (RNase H) inhibitor. In particular, its conversion to a 2-aryl-cycloheptathienoozaxinone derivative and the successive thorough exploration of both 2-aromatic and cycloheptathieno moieties led to identify oxazinone-based compounds as new anti-RNase H chemotypes. The presence of the catechol moiety at the C-2 position of the scaffold emerged as critical to achieve potent anti-RNase H activity, which also encompassed anti-RNA dependent DNA polymerase (RDDP) activity for the tricyclic derivatives. Benzothienooxazinone derivative 22 resulted the most potent dual inhibitor exhibiting IC50s of 0.53 and 2.90 μM against the RNase H and RDDP functions. Mutagenesis and docking studies suggested that compound 22 binds two allosteric pockets within the RT, one located between the RNase H active site and the primer grip region and the other close to the DNA polymerase catalytic centre.
- Massari, Serena,Corona, Angela,Distinto, Simona,Desantis, Jenny,Caredda, Alessia,Sabatini, Stefano,Manfroni, Giuseppe,Felicetti, Tommaso,Cecchetti, Violetta,Pannecouque, Christophe,Maccioni, Elias,Tramontano, Enzo,Tabarrini, Oriana
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- Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D2 receptor
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We recently described a structurally novel series of negative allosteric modulators (NAMs) of the dopamine D2 receptor (D2R) based on thieno[2,3-d]pyrimidine 1, showing it can be structurally simplified to reveal low molecular weight, fragment-like NAMs that retain robust negative cooperativity, such as 3. Herein, we report the synthesis and functional profiling of analogues of 3, placing specific emphasis on examining secondary and tertiary amino substituents at the 4-position, combined with a range of substituents at the 5/6-positions (e.g. aromatic/aliphatic carbocycles). We identify analogues with diverse pharmacology at the D2R including NAMs with sub-μM affinity (9h) and, surprisingly, low efficacy partial agonists (9d and 9i).
- Fyfe, Tim J.,Kellam, Barrie,Mistry, Shailesh N.,Scammells, Peter J.,Lane, J. Robert,Capuano, Ben
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p. 474 - 490
(2019/03/07)
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- One-Pot Synthesis of Thieno[3,2- e]pyrrolo[1,2- a]pyrimidine Derivative Scaffold: A Valuable Source of PARP-1 Inhibitors
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A new, efficient, and versatile one-pot cascade reaction of diverse Gewald's aminothiophenes, 2-hydroxy-4-oxobut-2-enoic acid, and derivatives of cyanoacetic acid catalyzed by Et3N is presented. It enables direct synthesis of diverse 1-(2-oxoethylidene)-2-oxothieno[3,2-e]pyrrolo[1,2-a]pyrimidine in good to excellent yields. The reaction exhibits a broad substrate scope and also presents an opportunity for further modification of the structure. The method offers a convenient practical alternative to the known procedures. The synthesized thieno[3,2-e]pyrrolo[1,2-a]pyrimidine scaffold is an important structural motif of new poly(ADP-ribose) polymerase (PARP) inhibitors, playing a useful role in multiple pharmacological applications.
- Shipilovskikh, Sergei A.,Rubtsov, Aleksandr E.
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supporting information
p. 15788 - 15796
(2019/12/25)
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- Identification of 4-methoxythieno[2,3-d]pyrimidines as FGFR1 inhibitors
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Aim. To identify novel FGFR1 inhibitors using virtual screening approach. Methods. We used methods of organic synthesis, molecular docking via the Autodock 4.2.6 program package and in vitro biochemical tests with γ-32P. Results. In vitro experiments showed that 9 of 23 tested compounds possess inhibitory activity against FGFR1 with IC50 values in the range from 0.9 to 5.6 μM. Conclusions. Nine FGFR1 inhibitors were developed. The mode of compounds binding with the ATP-acceptor site was determined using molecular docking methods and the dependence of the compounds’ activity on the substituents R1, R4 and R5 was evaluated.
- Balanda, A. O.,Bdzhola, V. G.,Kotey, I. M.,Pletnova, L. V.,Protopopov, M. V.,Prykhod’ko, A. O.,Starosyla, S. A.,Yarmoluk, S. M.
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p. 152 - 162
(2020/06/02)
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- COMPOUND FOR INHIBITING THE GROWTH AND PROLIFERATION OF HUMAN LIVER CANCER CELLS AND METHOD FOR SYNTHESIZING IT
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The compound 2-((4-nitrophenyl)amino)-6,7,8,9-tetrahydro-3H-cyclohepta[4,5]thieno[2, 3-d]pyrimidin-4(5H)-one and method of synthesizing it, wherein the compound is effective to inhibit the growth and proliferation of human liver cancer cells HepG2. The compound has an inhibitory concentration value (IC50) of 0.7 μg, compared to reference medication Doxorubicin that has an (IC50) value of 1.2 μg. It further surpasses that reference medication Doxorubicin at all tested concentraions. The method includes the steps of: preparing a first compound of cycloheptanone, ethyl cyanoacetate, sulfur, ethanol and diethyl amine; preparing a second compound by heating of the first compound with excess of hydrazine hydrate in absolute ethanol as solvent; and preparing the effective compound of the invention by reaction of the second chemical compound with 4-nitrophenylisothiocyanate in dry dimethylformamide as solvent.
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Paragraph 00051-00056
(2018/04/20)
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- A CHEMICAL COMPOUND FOR INHIBITING THE GROWTH AND PROLIFERATION OF HUMAN LIVER CANCER CELLS HEPG2 AND METHOD FOR SYNTHESIZING IT
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The compound 2-((4-Nitrophenyl)amino)-7,8,9,10-tetrahydrocyclohepta[4,5]thieno[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-11(6H)-one and method of synthesizing it, wherein the compound is effective to inhibit the growth and proliferation of human liver cancer cells HepG2. The compound has a higher efficiency to inhibit the growth and proliferation of these cells as it has an inhabitation concentration value (IC50) of 0.7 μg, compared to reference medication Doxorubicin that has an (IC50) value of 1.2 μg. It further surpasses that reference medication at all tested concentrations. The method includes the steps of: preparing a first compound of cycloheptanone, ethylcyanoacetate, sulfur, ethanol and diethylamine; preparing a second compound by heating of the first compound with hydrazine hydrate in absolute ethanol as solvent; preparing a third compound by heating the second compound with carbon disulphide in pyridine; and preparing the compound of the invention by reacting the third compound with 4-nitrophenylisothiocyanate in dimethylformamide as solvent.
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Paragraph 00028; 00051-00055; 00082
(2018/09/25)
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- Design and synthesis of novel annulated thienopyrimidines as phosphodiesterase 5 (PDE5) inhibitors
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Novel cycloalkene-fused thienopyrimidine analogues with enhanced phosphodiesterase 5 (PDE5) inhibitory properties are presented. The structure of the reported scaffold was modulated through variation of the terminal cycloalkene ring size, as well as by va
- El-Sharkawy, Lina Y.,El-Sakhawy, Rowaida A.,Abdel-Halim, Mohammad,Lee, Kevin,Piazza, Gary A.,Ducho, Christian,Hartmann, Rolf W.,Abadi, Ashraf H.
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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, 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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- Discovery of a Small-Molecule Bromodomain-Containing Protein 4 (BRD4) Inhibitor That Induces AMP-Activated Protein Kinase-Modulated Autophagy-Associated Cell Death in Breast Cancer
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Upon the basis of The Cancer Genome Atlas (TCGA) data set, we identified that several autophagy-related proteins such as AMP-activated protein kinase (AMPK) were remarkably downregulated in breast cancer. Combined with coimmunoprecipitation assay, we demonstrated that BRD4 might interact with AMPK. After analyses of the pharmacophore and WPF interaction optimization, we designed a small-molecule inhibitor of BRD4, 9f (FL-411) which was validated by cocrystal structure with BD1 of BRD4. Subsequently, 9f was discovered to induce ATG5-dependent autophagy-associated cell death (ACD) by blocking BRD4-AMPK interaction and thus activating AMPK-mTOR-ULK1-modulated autophagic pathway in breast cancer cells. Interestingly, the iTRAQ-based proteomics analyses revealed that 9f induced ACD pathways involved in HMGB1, VDAC1/2, and eEF2. Moreover, 9f displayed a therapeutic potential on both breast cancer xenograft mouse and zebrafish models. Together, these results demonstrate that a novel small-molecule inhibitor of BRD4 induces BRD4-AMPK-modulated ACD in breast cancer, which may provide a candidate drug for future cancer therapy.
- Ouyang, Liang,Zhang, Lan,Liu, Jie,Fu, Leilei,Yao, Dahong,Zhao, Yuqian,Zhang, Shouyue,Wang, Guan,He, Gu,Liu, Bo
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p. 9990 - 10012
(2017/12/15)
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- A Thieno[2,3- d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D2 Receptor
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Recently, a novel negative allosteric modulator (NAM) of the D2-like dopamine receptors 1 was identified through virtual ligand screening. This ligand comprises a thieno[2,3-d]pyrimidine scaffold that does not feature in known dopaminergic ligands. Herein, we provide pharmacological validation of an allosteric mode of action for 1, revealing that it is a NAM of dopamine efficacy and identify the structural determinants of this allostery. We find that key structural moieties are important for functional affinity and negative cooperativity, while functionalization of the thienopyrimidine at the 5- and 6-positions results in analogues with divergent cooperativity profiles. Successive compound iterations have yielded analogues exhibiting a 10-fold improvement in functional affinity, as well as enhanced negative cooperativity with dopamine affinity and efficacy. Furthermore, our study reveals a fragment-like core that maintains low μM affinity and robust negative cooperativity with markedly improved ligand efficiency.
- Fyfe, Tim J.,Zarzycka, Barbara,Lim, Herman D.,Kellam, Barrie,Mistry, Shailesh N.,Katrich, Vsevolod,Scammells, Peter J.,Lane, J. Robert,Capuano, Ben
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p. 174 - 206
(2018/05/14)
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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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- Synthesis, antimicrobial, antiquorum-sensing, antitumor and cytotoxic activities of new series of cyclopenta(hepta)[b]thiophene and fused cyclohepta[b]thiophene analogs
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New series of cyclopenta(hepta)[b]thiophene and fused cyclohepta[b]thiophene analogs were synthesized. The new analogs were assessed for antibacterial efficacy toward Escherichia coli ATCC 12435, Bacillus cereus UW 85 and Staphylococcus aureus. Compounds
- Abdel-Rahman, Somaya A.,El-Gohary, Nadia S.,El-Bendary, Eman R.,El-Ashry, Saadia M.,Shaaban, Mona I.
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p. 200 - 211
(2017/09/20)
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- BRD4 inhibitors and applications thereof in tumor treating medicines
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The invention relates to BRD4 targeting inhibitors and applications thereof in tumor treating medicines, and belongs to the technical field of antitumor pharmacy. A technical problem to be overcome is to provide compounds adopted as the BRD4 inhibitors. The compounds include compounds shown as follows, or pharmaceutically acceptable salts thereof. The compounds or the pharmaceutically acceptable salts thereof can be adopted as the BRD4 inhibitors and have obvious breast cancer treating effects.
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Paragraph 0067-0069
(2017/07/19)
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- COMPOUND FOR THE TREATMENT OF HUMAN LIVER CANCER AND METHOD FOR SYNTHESIZING IT
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The compound “2-((4-nitrophenyl)amino)-7,8,9,10-tetrahydro cyclohepta[4,5]thieno[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-11(6H)-one” and method of synthesizing it, wherein the compound is effective to inhibit the growth and proliferation of human liver cancer cells HepG2. The compound has a higher efficiency to inhibit the growth and proliferation of these cells as it has an inhibitory concentration value (IC50) of 0.7 μg, compared to reference medication Doxorubicin that has an (IC50) value of 1.2 μg. It further surpasses that reference medication at all tested concentrations. The method includes the steps of: preparing a first compound of cycloheptanone, ethylcyanoacetate, sulfur, ethanol and diethylamine; preparing a second compound by heating of the first compound with excess of hydrazine hydrate in absolute ethanol as solvent; preparing a third compound by heating the second compound with carbon disulphide in dry pyridine; and preparing the compound of the invention by reacting the third compound with 4-nitrophenylisothiocyanate in dry N,N-methylformamide as solvent.
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Page/Page column 3
(2016/08/17)
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- COMPOUND FOR INHIBITING THE GROWTH AND PROLIFERATION OF HUMAN LIVER CANCER CELLS AND METHOD FOR SYNTHESIZING IT
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The compound “2-((4-nitrophenyl)amino)-6,7,8,9-tetrahydro-3H-cyclohepta[4,5]thieno-[2,3-d]pyrimidin-4(5H)-one” and method of synthesizing it, wherein the compound is effective to inhibit the growth and proliferation of human liver cancer cells HepG2. The compound has an inhibitory concentration value (IC50) of 0.7 μg, compared to reference medication Doxorubicin that has an (IC50) value of 1.2 μg. It further surpasses that reference medication Doxorubicin at all tested concentraions. The method includes the steps of: preparing a first compound of cycloheptanone, ethylcyanoacetate, sulfur, ethanol and diethyl amine; preparing a second compound by heating of the first compound with excess of hydrazine hydrate in absolute ethanol as solvent; and preparing the effective compound of the invention by reaction of the second chemical compound with 4-nitrophenylisothiocyanate in dry dimethylformamide as solvent.
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Paragraph 0053-0058
(2016/10/17)
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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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- 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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- Ligand-free Pd-catalyzed C-N cross-coupling/cyclization strategy: An unprecedented access to 1-thienyl pyrroloquinoxalines for the new approach towards apoptosis
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The link between PDE4 and apoptosis prompted us to design and synthesize for the first time a series of novel 1-thienyl pyrroloquinoxalines as potential PDE4 inhibitors/apoptotic agents. A ligand-free Pd-catalyzed C-N cross-coupling/cyclization strategy h
- Kolli, Sunder Kumar,Nakhi, Ali,Archana, Sivakumar,Saridena, Maneesha,Deora, Girdhar Singh,Yellanki, Swapna,Medisetti, Raghavender,Kulkarni, Pushkar,Ramesh Raju,Pal, Manojit
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supporting information
p. 270 - 278
(2014/09/29)
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- FLT3 INHIBITORS AND USES THEREOF
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The present invention provides methods of using compounds of formula I: or compositions thereof for the inhibition of FLT3, and the treatment of FLT3-mediated disorders.
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Paragraph 00639-00640
(2014/12/12)
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- Facile assembly of two 6-membered fused N-heterocyclic rings: A rapid access to novel small molecules via Cu-mediated reaction
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A rapid, versatile and one-pot Cu-mediated domino reaction has been developed for facile assembly of two six membered fused N-heterocyclic rings leading to novel small molecules as potential inhibitors of PDE4. The Royal Society of Chemistry.
- Adepu, Raju,Sunke, Rajnikanth,Meda, Chandana L. T.,Rambabu,Krishna, G. Rama,Reddy, C. Malla,Deora, Girdhar Singh,Parsa, Kishore V. L.,Pal, Manojit
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supporting information
p. 190 - 192
(2013/02/22)
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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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- PROTEASOME ACTIVITY MODULATING COMPOUNDS
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The present invention is directed to compounds having the Formula (I), (la) or (Ib), compositions thereof and methods for the treatment of a condition associated with a dysfunction in proteostasis.
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Page/Page column 67
(2013/08/15)
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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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- Thieno[3,2-c]pyran-4-one based novel small molecules: Their synthesis, crystal structure analysis and in vitro evaluation as potential anticancer agents
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Novel thieno[3,2-c]pyran-4-one based small molecules were designed as potential anticancer agents. Expeditious synthesis of these compounds was carried out via a multi-step sequence consisting of few steps such as Gewald reaction, Sandmeyer type iodination, Sonogashira type coupling followed by iodocyclization and then Pd-mediated various C-C bond forming reactions. The overall strategy involved the construction of thiophene ring followed by the fused pyranone moiety and then functionalization at C-7 position of the resultant thieno[3,2-c]pyran-4-one framework. Some of the compounds synthesized showed selective growth inhibition of cancer cells in vitro among which two compounds for example, 5d and 6c showed IC50 values in the range of 2.0-2.5 μM. The crystal structure analysis of an active compound along with hydrogen bonding patterns and molecular arrangement present within the molecule is described.
- Nakhi, Ali,Adepu, Raju,Rambabu,Kishore, Ravada,Vanaja,Kalle, Arunasree M.,Pal, Manojit
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supporting information; experimental part
p. 4418 - 4427
(2012/09/07)
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- Synthesis and biological evaluation of thiophene derivatives as acetylcholinesterase inhibitors
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A series of new thiophene derivatives has been synthesized using the Gewald protocol. The acetylcholinesterase inhibition activity was assayed according to Ellman's method using donepezil as reference. Some of the compounds were found to be more potent inhibitors than the reference. 2-(2-(4-(4-Methoxyphenyl) piperazin-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (IIId) showed 60% inhibition, compared to only 40% inhibition by donepezil.
- Ismail, Mohamed M.,Kamel, Mona M.,Mohamed, Lamia W.,Faggal, Samar I.,Galal, Mai A.
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scheme or table
p. 7217 - 7231
(2012/09/22)
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- C-C (alkynylation) vs C-O (ether) bond formation under Pd/C-Cu catalysis: Synthesis and pharmacological evaluation of 4-alkynylthieno[2,3-d]pyrimidines
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The Pd/C-CuI-PPh3 catalytic system facilitated C-C bond formation between 4-chlorothieno[2,3-d]pyrimidines and terminal alkynes in methanol with high selectivity without generating any significant side products arising from C-O bond formation b
- Gorja, Dhilli Rao,Shiva Kumar,Mukkanti,Pal, Manojit
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scheme or table
p. 338 - 345
(2011/06/18)
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- Sequential coupling/desilylation-coupling/cyclization in a single pot under Pd/C-Cu catalysis: Synthesis of 2-(hetero)aryl indoles
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A new one-pot synthesis of 2-(hetero)aryl indoles via sequential C-C coupling followed by C-Si bond cleavage and a subsequent tandem C-C/C-N bond forming reaction is described. A variety of functionalized indole derivatives were prepared by conducting thi
- Rao, R. Mohan,Reddy Ch, Upendar,Alinakhi,Mulakayala, Naveen,Alvala, Mallika,Arunasree,Poondra, Rajamohan R.,Iqbal, Javed,Pal, Manojit
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scheme or table
p. 3808 - 3816
(2011/06/21)
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- The synthesis and biological evaluation of 2-amino-4,5,6,7,8,9- hexahydrocycloocta[b]thiophenes as allosteric modulators of the A1 adenosine receptor
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A series of 2-amino-4,5,6,7,8,9-hexahydrocycloocta[b]thiophenes were prepared and evaluated as potential allosteric modulators of the A1 adenosine receptor (AR). The structure-activity relationships of the 3-position were explored along with va
- Aurelio, Luigi,Christopoulos, Arthur,Flynn, Bernard L.,Scammells, Peter J.,Sexton, Patrick M.,Valant, Celine
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supporting information; experimental part
p. 3704 - 3707
(2011/08/06)
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- Identification of 5,6-substituted 4-aminothieno[2,3-d]pyrimidines as LIMK1 inhibitors
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4-Aminobenzothieno[3,2-d]pyrimidines were previously identified in a high throughput screening campaign as LIMK1 inhibitors. Scaffold reversal led to the identification of a series of simple 5,6-substituted 4-aminothieno[2,3-d] pyrimidines with low micromolar inhibition of LIMK1.
- Sleebs, Brad E.,Nikolakopoulos, George,Street, Ian P.,Falk, Hendrik,Baell, Jonathan B.
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supporting information; experimental part
p. 5992 - 5994
(2011/10/18)
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- Synthesis and anti-tumor activities of N′-benzylidene-2-(4- oxothieno[2,3-d]pyrimidin-3(4H)-yl)acetohydrazone derivatives
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A compound with a cyclic thienopyrimidine moiety and an aceto-hydrazone moiety in its chemical structure was discovered in a cell-based screening to have noticeable cytotoxicity on several tumor cell lines. A total of 38 derivatives of this compound were
- Lou, Jiangping,Liu, Zhen,Li, Yan,Zhou, Mi,Zhang, Zhengxi,Zheng, Shu,Wang, Renxiao,Li, Jian
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supporting information; experimental part
p. 6662 - 6666
(2011/12/04)
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- Convenient synthesis of 2-aminothiophene derivatives by acceleration of gewald reaction under ultrasonic aqueous conditions
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Under ultrasound irradiation and in the presence of H2O/Et 2NH, ethyl cyanoacetate or malononitrile can combine with-methylene carbonyl compounds and elemental sulfur to efficiently yield 2-aminothiophene derivatives within a few minutes. Products are easily obtained by simple filtration because of their spontaneous precipitation in the reaction mixtures. Copyright Taylor & Francis Group, LLC.
- Mojtahedi, Mohammad M.,Abaee, M. Saeed,Mahmoodi, Peyman,Adib, Mehdi
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experimental part
p. 2067 - 2074
(2010/08/13)
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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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- Synthesis and pharmacological evaluation of novel fused thiophene derivatives as 5-HT2A receptor antagonists: Molecular modeling study
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Novel derivatives of cyclopentathienopyrimidinediones 6, pyridothienopyrimidinediones 7, ethyl cycloheptathiophene-3-carboxylates 10, ethyl tetrahydrothienopyridine-3-carboxylates 11, tetrahydrocycloheptathienopyrimidin-4(3H)-ones 12, tetrahydrotriazolobenzothienopyrimidin-5(4H)-ones 17 and tetrahydro-5H-cycloheptathienopyrimidin-4(3H)-ones 21 have been synthesized and tested for their?5-HT2A antagonist activity. Preliminary pharmacological studies showed that compounds 3-[2-[4-phenylpiperazin-1-yl]ethyl]-6,7-dihydro-5H-cyclopenta[b]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione 6a and ethyl 2-[[4-(2-methoxyphenyl)piperazin-1-yl]acetylamino]-4,5,6,7-tetrahydro-6-methylthieno[2,3-c]pyridine-3-carboxylate 11d were found to be the most active molecules as 5-HT2A antagonists. Molecular modeling and pharmacophore prediction methodology are used to study the structural features required for 5-HT2A antagonist properties of the active compounds compared with nonactive species by means of the molecular mechanic method. The 2-methoxy substituent in the structure of 11d seems to be necessary for its full antagonistic properties. Optimal placement of basic nitrogen relative to the plane of thiophene core was found to have a profound effect on affinity and biological activity.
- El-Kerdawy, Mohamed M.,El-Bendary, Eman R.,Abdel-Aziz, Alaa A.-M.,El-wasseef, Dalia R.,El-Aziz, Naglaa I. Abd
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body text
p. 1805 - 1820
(2010/06/21)
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- Synthesis and antitumor evaluation of novel diarylsulfonylurea derivatives: Molecular modeling applications
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Some new ethyl 2-[3-(4-unsubstituted or 4-substituted phenylsufonyl)ureido]-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylates 3a-c, 2-[3-(phenylsulfonyl)ureido]-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carbohydrazides 4a-f, 3-phenylsulfony
- El-Sherbeny, Magda A.,Abdel-Aziz, Alaa A.-M.,Ahmed, Musa A.
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body text
p. 689 - 697
(2010/04/04)
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- NOVEL COMPOUNDS AS CANNABINOID RECEPTOR LIGANDS
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The present application relates to cannabinoid receptor ligands containing compounds of formula (I) wherein A, R1, R2, and R3 are as defined in the specification. The present application also relates to compositions comprising such compounds, and methods of treating conditions and disorders using such compounds and compositions.
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Page/Page column 43
(2009/01/24)
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- Synthesis and antimicrobial activity of some new derivatives of thieno [2,3-i/] Pyrimidin-4 (l//)-one and 1,2,41 triazolo [4,3-fl] thienopyrimidin -5-ones
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ETHYL 2-AMINOCYCLOALKA[6]thiophene-3-carboxylate 1-3 was used as precursor for the preparation of some novel cycloalka [b]thieno [2,3-d] - 3,4-dihydropyrimidin- 4 (1H)-one 8-10, ethyl 2-[(2thienylcarbonyl) amino] - 5, 6-dihydro-4//-[6]thiophene-3 carboxylate 12-14 and [1, 2, 4] triazolo [4, 3-a] thieno - pyrimidine - 5(1H) - one derivatives 20. These compounds were prepared by treating compounds 1-3 with each of ethyl N-phenylhydrazonochloroacetate 4 or thiophenc-2-carbonylchloride 11 and cycloalka[b]thieno[2,3-d]-3,4dihydro- pyrimidin-4-one or its methyl thio 21 with each of the hydazonoyl halides4,12.
- Mahran, Asma M.
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body text
p. 539 - 553
(2010/10/03)
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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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- Efficient synthesis of substituted 2-amino-3-carbethoxythiophenes
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A microwave-assisted method for the synthesis of a variety of thiophene o-aminoesters (2a-l) has been developed, starting from an appropriate aldehyde, methyl ketone or acetoacetate ester with ethyl cyanoacetate in the presence of elemental sulfur. Copyright Taylor & Francis Group, LLC.
- Kathiravan,Shishoo,Chitre,Mahadik,Jain
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p. 4273 - 4279
(2008/03/13)
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- Synthesis and SAR of thiophene containing kinesin spindle protein (KSP) inhibitors
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We have identified and synthesized a series of thiophene containing inhibitors of kinesin spindle protein. SAR studies led to the synthesis of 33, which was co-crystallized with KSP and determined to bind to an allosteric pocket previously described for o
- Pinkerton, Anthony B.,Lee, Tom T.,Hoffman, Timothy Z.,Wang, Yan,Kahraman, Mehmet,Cook, Travis G.,Severance, Daniel,Gahman, Timothy C.,Noble, Stewart A.,Shiau, Andrew K.,Davis, Robert L.
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p. 3562 - 3569
(2008/12/23)
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- Synthesis and reactions of some new substituted pyridine and pyrimidine derivatives as analgesic, anticonvulsant and antiparkinsonian agents
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A series of substituted pyridine and pyrimidine derivatives were synthesized as analgesic, anti-convulsant, and antiparkinsonian agents by using compounds 1, 2, and 9 as starting materials. Pyridino-imide derivative 3 was prepared by condensation of 1 wit
- Amr, Abd El-Galil E.,Sayed, Hayam H.,Abdulla, Mohamed M.
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p. 433 - 440
(2007/10/03)
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- Synthesis and analgesic activities of some 2-(benzazolylacetyl)amino-3- ethoxycarbonylthiophene derivatives
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In this study, some 2-[2-(benzazole-2-thioxy)acetylamino]-3- ethoxycarbonylthiophene and 2-[2-(benzazole-1-yl)acetylamino]-3- ethoxycarbonylthiophene compounds were obtained by the reaction of 2-chloroacetylamino-3-ethoxycarbonylthiophene derivatives and a suitable benzazole-2-thione or benzimidazole derivatives. Analgesic activities of the compounds were tested by using tail-flick and tail-immersion methods. It is reported that some of the compounds showed remarkable analgesic activities. Copyright Taylor & Francis Inc.
- Demirayak, Seref,Karaburun, Ahmet C.,Kayagil, Ismail,Ucucu, Umit,Beis, Rana
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p. 1841 - 1848
(2007/10/03)
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