- COMPOUNDS WITH COPPER- OR ZINC-ACTIVATED TOXICITY AGAINST MICROBIAL INFECTION
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Heterocyclic compounds with a novel pyrazole thioamide-based NNSN structural motif, having highly effective zinc- or copper-activated toxicity against microbial infections at micromolar or nanomolar minimum inhibitory concentrations (MIC), and methods of making and using same.
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- Microwave mediated synthesis of 2-aminooxazoles
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A microwave mediated synthesis of 2-aminooxazoles at 150 °C was developed, providing products with a variety of functional groups. The reaction takes 5 min and provides product with a simple precipitation at moderate to good yields without the need for recrystallization or flash chromatography.
- Cronin, Adam,Eagon, Scott,Gleason, Cameron,Johnson, Hunter,Kimball, Joshua J.,Klug, Trevan,Lazaro, Horacio,Liyanage, Duminda,Manjunath, Aashrita,O'Brien, Eli,Schioldager, Ryan,Schmid, Connor,Soderberg, Nathan
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- NaOH-promoted one-pot aryl isothiocyanate synthesis under mild benchtop conditions
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In this work, we have established a green synthesis of aryl isothiocyanates promoted by the low-cost and readily available NaOH from aryl amines and carbon disulfide in a one-pot procedure. The developed protocol features no extra desulfurating reagents and mild benchtop conditions, in which NaOH serves as both the base and the desulfurating reagent to decompose the dithiocarbamate intermediate. Fourteen examples of aryl amines bearing electronic neutral, rich and poor substituents, as well as benzylamine, have proved to be compatible substrates in the developed method to furnish the corresponding isothiocyanates. The reaction has been performed on a gram scale to further demonstrate its synthetic utility. Compared to the reported base-promoted synthesis of aryl isothiocyanates that requires the use of special equipment, such as the ball mill or the microwave reactor, the simplicity in operation and scalability enables this method to efficiently access a variety of aryl isothiocyanates.
- Li, Hang,Liu, Xinyun,Yin, Xiaogang
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supporting information
p. 839 - 844
(2021/05/27)
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- Synthesis of isothiocyanates using DMT/NMM/TsO? as a new desulfurization reagent
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Thirty-three alkyl and aryl isothiocyanates, as well as isothiocyanate derivatives from esters of coded amino acids and from esters of unnatural amino acids (6-aminocaproic, 4-(aminomethyl)benzoic, and tranexamic acids), were synthesized with satisfactory or very good yields (25–97%). Synthesis was performed in a “one-pot”, two-step procedure, in the presence of organic base (Et3 N, DBU or NMM), and carbon disulfide via dithiocarbamates, with 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium toluene-4-sulfonate (DMT/NMM/TsO? ) as a desulfurization reagent. For the synthesis of aliphatic and aromatic isothiocyanates, reactions were carried out in a microwave reactor, and selected alkyl isothiocyanates were also synthesized in aqueous medium with high yields (72–96%). Isothiocyanate derivatives of L-and D-amino acid methyl esters were synthesized, under conditions without microwave radiation assistance, with low racemization (er 99 > 1), and their absolute configuration was confirmed by circular dichroism. Isothiocyanate derivatives of natural and unnatural amino acids were evaluated for antibacterial activity on E. coli and S. aureus bacterial strains, where the most active was ITC 9e.
- Janczewski, ?ukasz,Kolesińska, Beata,Kr?giel, Dorota
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- A catalyst-free method for the synthesis of 1,4,2-dithiazoles from isothiocyanates and hydroxylamine triflic acid salts
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A catalyst-free method for the preparation of 1,4,2-dithiazoles is developed by reactions of isothiocyanates with hydroxylamine triflic acid salts. This reaction achieves C-S, C-N, and S-N bond formation, and a range of products are obtained in moderate to good yields. The obvious feature is using shelf-stable hydroxylamine triflic acid salts as a N source to synthesize heterocycles under mild conditions.
- An, Zhenyu,Liu, Yafeng,Ren, Yi,Wang, Ting,Yan, Rulong
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supporting information
p. 6206 - 6209
(2021/07/28)
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- Diaryl-substituted thiosemicarbazone: A potent scaffold for the development of New Delhi metallo-β-lactamase-1 inhibitors
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The superbug infection caused by New Delhi metallo-β-lactamase (NDM-1) has become an emerging public health threat. Inhibition of NDM-1 has proven challenging due to its shuttling between pathogenic bacteria. A potent scaffold, diaryl-substituted thiosemicarbazone, was constructed and assayed with metallo-β-lactamases (MβLs). The obtained twenty-six molecules specifically inhibited NDM-1 with IC50 0.038–34.7 μM range (except 1e, 2e, and 3d), and 1c is the most potent inhibitor (IC50 = 0.038 μM). The structure-activity relationship of synthetic thiosemicarbazones revealed that the diaryl-substitutes, specifically 2-pyridine and 2-hydroxylbenzene improved inhibitory activities of the inhibitors. The thiosemicarbazones exhibited synergistic antimycobacterial actions against E. coli-NDM-1, resulted a 2–512-fold reduction in MIC of meropenem, while 1c restored 16–256-, 16-, and 2-fold activity of the antibiotic on clinical isolates ECs, K. pneumonia and P. aeruginosa harboring NDM-1, respectively. Also, mice experiments showed that 1c had a synergistic antibacterial ability with meropenem, reduced the bacterial load clinical isolate EC08 in the spleen and liver. This work provided a highly promising scaffold for the development of NDM-1 inhibitors.
- Li, Jia-Qi,Sun, Le-Yun,Jiang, Zhihui,Chen, Cheng,Gao, Han,Chigan, Jia-Zhu,Ding, Huan-Huan,Yang, Ke-Wu
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- Discovery of boronic acid-based potent activators of tumor pyruvate kinase M2 and development of gastroretentive nanoformulation for oral dosing
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Several studies have established that cancer cells explicitly over-express the less active isoform of pyruvate kinase M2 (PKM2) is critical for tumorigenesis. The activation of PKM2 towards tetramer formation may increase affinity towards phosphoenolpyruvate (PEP) and avoidance of the Warburg effect. Herein, we describe the design, synthesis, and development of boronic acid-based molecules as activators of PKM2. The designed molecules were inspired by existing anticancer scaffolds and several fragments were assembled in the derivatives. 6a-6d were synthesized using a multi-step synthetic strategy in 55–70% yields, starting from cheap and readily available materials. The compounds were selectively cytotoxic to kill the cancerous cells at 80 nM, while they were non-toxic to the normal cells. The kinetic studies established the compounds as novel activators of PKM2 and (E/Z)-(4-(3-(2-((4-chlorophenyl)amino)-4-(dimethylamino)thiazol-5-yl)-2-(ethoxycarbonyl)-3-oxoprop-1-en-1-yl) phenyl)boronic acid (6c) emerged as the most potent derivative. 6c was further evaluated using various in silico tools to understand the molecular mechanism of tetramer formation. Docking studies revealed that 6c binds to the PKM2 dimer at the dimeric interface. Further to ascertain the binding site and mechanism of action, rigorous MD (molecular dynamics) simulations were undertaken, which led to the conclusion that 6c stabilizes the center of the dimeric interface that possibly promotes tetramer formation. We further planned to make a tablet of the developed molecule for oral delivery, but it was seriously impeded owing to poor aqueous solubility of 6c. To improve aqueous solubility and retain 6c at the lower gastrointestinal tract, thiolated chitosan-based nanoparticles (TCNPs) were prepared and further developed as tablet dosage form to retain anticancer potency in the excised goat colon. Our findings may provide a valuable pharmacological mechanism for understanding metabolic underpinnings that may aid in the clinical development of new anticancer agents targeting PKM2.
- Patle, Rajkumar,Shinde, Shital,Patel, Sagarkumar,Maheshwari, Rahul,Jariyal, Heena,Srivastava, Akshay,Chauhan, Neelam,Globisch, Christoph,Jain, Alok,Tekade, Rakesh K.,Shard, Amit
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supporting information
(2021/05/19)
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- Design, synthesis and biological evaluation of novel 2,4-disubstituted quinazoline derivatives targeting H1975 cells via EGFR-PI3K signaling pathway
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In order to find new and highly effective anti-tumor drugs with targeted therapeutic effects, a series of novel 4-aminoquinazoline derivatives containing N-phenylacetamide structure were designed, synthesized and evaluated for antitumor activity against four human cancer cell lines (H1975, PC-3, MDA-MB-231 and MGC-803) using MTT assay. The results showed that the compound 19e had the most potent antiproliferative activity against H1975, PC-3, MDA-MB-231 and MGC-803 cell lines. At the same time, compound 19e could significantly inhibit the colony formation and migration of H1975 cells. Compound 19e also arrested the H1975 cell cycle in the G1 phase and mediated cell apoptosis, promoted the accumulation of ROS in H1975 cells. Furthermore, compound 19e exerted antitumor effect in vitro by reducing the expression of anti-apoptotic protein Bcl-2 and increasing the pro-apoptotic protein Bax and p53. Mechanistically, compound 19e could significantly decreased the phosphorylation of EGFR and its downstream protein PI3K in H1975 cells. Which indicated that compound 19e targeted H1975 cell via interfering with EGFR-PI3K signaling pathway. Molecular docking showed that compound 19e could bind into the active pocket of EGFR. Those work suggested that compound 19e would have remarkable implications for further design of anti-tumor agents.
- Chao, Gao,Dai, Honglin,Ke, Yu,Li, Erdong,Lihong, Shan,Liu, Hongmin,Liu, Limin,Si, Xiaojie,Wang, Zhengjie,Yang, Zhang,Zhang, Luye,Zhang, Qiurong,Zheng, Jiaxin
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- Discovery of quinazoline derivatives as a novel class of potent and in vivo efficacious LSD1 inhibitors by drug repurposing
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Histone lysine-specific demethylase 1 (LSD1) is an important epigenetic modulator, and is implicated in malignant transformation and tumor pathogenesis in different ways. Therefore, the inhibition of LSD1 provides an attractive therapeutic target for cancer therapy. Based on drug repurposing strategy, we screened our in-house chemical library toward LSD1, and found that the EGFR inhibitor erlotinib, an FDA-approved drug for lung cancer, possessed low potency against LSD1 (IC50 = 35.80 μM). Herein, we report our further medicinal chemistry effort to obtain a highly water-soluble erlotinib analog 5k (>100 mg/mL) with significantly enhanced inhibitory activity against LSD1 (IC50 = 0.69 μM) as well as higher specificity. In MGC-803 cells, 5k suppressed the demethylation of LSD1, indicating its cellular activity against the enzyme. In addition, 5k had a remarkable capacity to inhibit colony formation, suppress migration and induce apoptosis of MGC803 cells. Furthermore, in MGC-803 xenograft mouse model, 5k treatment resulted in significant reduction in tumor size by 81.6% and 96.1% at dosages of 40 and 80 mg/kg/d, respectively. Our findings indicate that erlotinib-based analogs provide a novel structural set of LSD1 inhibitors with potential for further investigation, and may serve as novel candidates for the treatment of LSD1-overexpressing cancers.
- Li, Zhonghua,Li, Zhongrui,Ma, Jinlian,Miao, Jinxin,Qin, Tingting,Yang, Nian,Zhang, Xinhui,Zhang, Zhenqiang,Zhao, Taoqian,Zhao, Xuan
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- Synthetic (E)-3-phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium chloride derivatives as promising chemotherapy agents on cell lines infected with HTLV-1
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Synthesis of four compounds belonging to mesoionic class, (E)-3-phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium chloride derivatives (5a-d) and their biological evaluation against MT2 and C92 cell lines infected with human T-cell lymphotropic virus type-1 (HTLV-1), which causes adult T-cell leukemia/lymphoma (ATLL), and non-infected cell lines (Jurkat) are reported. The compounds were obtained by convergent synthesis under microwave irradiation and the cytotoxicity was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Results showed IC50 values of all compounds in the range of 1.51-7.70 μM in HTLV-1-infected and non-infected cells. Furthermore, it was observed that 5b could induce necrosis after 24 h for Jurkat and MT2 cell lines. The experimental (fluorimetric method) and theoretical (molecular docking) results suggested that the mechanism of action for 5b could be related to its capacity to intercalate into DNA. Moreover, the preliminary pharmacokinetic profile of the studied compounds (5a-d) was obtained through human serum albumin (HSA) binding affinity using multiple spectroscopic techniques (circular dichroism, steady-state and time-resolved fluorescence), zeta potential and molecular docking calculations. The interaction HSA:5a-d is spontaneous and moderate (Ka ~ 104 M-1) via a ground-state association, without significantly perturbing both the secondary and surface structures of the albumin in the subdomain IIA (site I), indicating feasible biodistribution in the human bloodstream.
- Chaves, Otávio Augusto,De Oliveira, Thais Silva,Echevarria, Aurea,Echevarria-Lima, Juliana,Netto-Ferreira, José C.,Paiva, Rojane O.,Sousa-Pereira, Danilo
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- Synthesis of thiocarbamoyl fluorides and isothiocyanates using amines with CF3SO2Cl
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A practical and efficient method to synthesize thiocarbamyl fluorides and isothiocyanates from amines with trifluoromethanesulfonyl chloride was developed. In the presence of the reducing agent triphenylphosphine and sodium iodide, thiocarbamyl fluorides and isothiocyanates were synthesized from secondary/primary amine in moderate to excellent yields, respectively. A broad scope of substrates and good functional group compatibility were observed.
- Jiang, Lvqi,Yi, Wenbin,Wei, Jingjing,Liang, Shuaishuai
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p. 12374 - 12381
(2020/11/10)
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- Preparation method of phenyl isothiocyanate derivative
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The invention relates to a preparation method of a phenyl isothiocyanate derivative. The phenyl isothiocyanate derivative is prepared by the following preparation method: dissolving a phenyl chlorothioformate derivative and an aniline derivative in an organic solvent, taking cuprous iodide and a solid alkali as catalysts, performing heating reaction, and then performing purification to obtain thephenyl isothiocyanate derivative. According to the preparation method of the phenyl isothiocyanate derivative, disclosed by the invention, the raw materials are economical and easy to obtain; the yield of a target product obtained through one-step reaction is about 65-85%, and is greatly improved compared with that of a traditional phenyl thiochloroformate method. The preparation method disclosedby the invention can powerfully promote the production efficiency of phenyl isothiocyanate and derivatives thereof, and has a wide industrial prospect.
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Paragraph 0019-0024; 0037-0038; 0046
(2020/03/09)
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- Iron-promoted one-pot approach: Synthesis of isothiocyanates
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We have established a facile and versatile synthesis for the construction of isothiocyanates from their respective amines in the presence of an eco-friendly, inexpensive, easily available Iron catalyst under mild conditions. This reaction provides the target products through the formation of thiocarbamate salt as an intermediate. Both aromatic amines and aliphatic amines provided the respective target products in moderate to high yield under optimized reaction conditions. However, electron withdrawing substituents were difficult to give target product at room temperature, whereas, they obtained final products in good yield at moderate temperature. In addition, mechanistic studies were revealed that the synthetic route involved iron based subsequent reactions of addition and removal of sulfur.
- Pendem, Venkata Bhavanarushi,Nannapaneni, Madhavi
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p. 485 - 490
(2020/02/18)
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- Synthesis and biological evaluation of innovative thiourea derivatives as PHGDH inhibitors
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In order to discover novel compounds with inhibitory activity against 3-phosphoglycerate dehydrogenase (PHGDH), a series of thiourea derivatives were designed and synthesized based on the structural modification of compound 5d. Compound 5d emerged from the visual database of ChemDiv of 200,000 small molecules by docking score ranking. Inhibition experiments on PHGDH activity of newly synthesized compounds were performed in vitro. Compounds with more than 30percent inhibitory rate at 25?μM on PHGDH were screened for IC50 measurement. Anti-proliferative activity of 4a, 5a, 6e, 6n against A2780, MDA-MB-468, MDA-MB-231 and HEK293T in vitro was evaluated. The results showed that the compound 4a displayed the best inhibitory activity on PHGDH among the newly synthesized compounds, and the compounds 4a, 5a, 6n had a better proliferation inhibition effect on human A2780 cell line than NCT-503 reported previously. In addition, 2D interaction diagrams revealed potential action modes of active compounds with PHGDH.
- Xiang, Jiawei,Tao, Lei,Zhou, Yue,Tan, Yuping,Li, Zicheng,Zhao, Yinglan,Sun, Qingxiang,Luo, Youfu
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p. 3873 - 3886
(2020/05/29)
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- Synthesis methods for isothiocyanate derivative
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The invention discloses synthesis methods for an isothiocyanate derivative. The first synthesis method includes reacting raw materials, including primary amine, trifluoromethyltrimethylsilane, potassium fluoride and sulfur, with an organic solvent at the room temperature to obtain the isothiocyanate derivative. The synthetic isothiocyanate derivative has the advantages of simple operation, safety,high efficiency, non-toxicity, low raw material price, mild condition, high yield, wide application range of substrates, high compatibility of functional groups and the like. The second synthesis method includes reacting raw materials, including the primary amine, silver trifluoromethane and potassium bromide, with the organic solvent at the room temperature to obtain the isothiocyanate derivative. The isothiocyanate derivative has the advantages of simple operation, safety, high efficiency, easy availability of the raw materials, nearly quantitative yield, wide application range of the substrates, applicability to selective post-modification of drugs or complex compounds, and the like.
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Paragraph 0033; 0034; 0035; 0036; 0049; 0050; 0051; 0052
(2019/05/22)
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- Design, synthesis, antiproliferative and antibacterial evaluation of quinazolinone derivatives
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A series of novel quinazolinone derivatives bearing a disulfide bond were designed and synthesized. Their in vitro antiproliferative activities were evaluated using CCK-8 assay against SMMC-7721, Hela, A549 and MCF-7 human cancer cell lines and normal cell lines L929. The preliminary bioassay results demonstrated that all compounds 7a–7h, 8a–8h and 9a–9h exhibited antiproliferation with various degrees, and some compounds showed better effects than positive control 5-fluorouracil against different cancer cell lines. Among these compounds, 8c and 9f showed significant antiproliferative activity against SMMC-7721 cells with IC50 values of 2.88 and 2.56 μM, respectively. In Hela cells, compounds 9c and 9d showed highly effective biological activity with IC50 values of 3.16 and 2.68 μM, respectively. Compounds 7a and 9a exhibited good inhibitory effect against A549 cells with IC50 values of 3.53 and 3.54 μM, respectively. In MCF-7 cells, compounds 7e, 8e and 9e displayed excellent activity with IC50 values of 1.26, 1.12 and 1.85 μM, respectively. Besides, most of the tested compounds showed low cytotoxic effect against the normal cell lines L929. Biological evaluation indicated that all the tested compounds possessed antibacterial activity with certain degrees.
- Wang, Hai-Xin,Liu, Hai-Ying,Li, Wei,Zhang, Shuai,Wu, Zheng,Li, Xin,Li, Cai-Wen,Liu, Yu-Ming,Chen, Bao-Quan
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p. 203 - 214
(2019/01/04)
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- Design, computational studies, synthesis and biological evaluation of thiazole-based molecules as anticancer agents
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Background: Abolition of cancer warrants effective treatment modalities directed towards specific pathways dysregulated in tumor proliferation and survival. The antiapoptotic Bcl-2 proteins are significantly altered in several tumor types which position them as striking targets for therapeutic intervention. Here we designed, computationally evaluated, synthesized, and biologically tested structurally optimized thiazole-based small molecules as anticancer agents. Methods: The virtually designed 200 molecules were subjected to rigorous docking and in silico ADME-Toxicity studies. Out of this, 23 skeletally diverse thiazole-based molecules which passed pan assay interference compounds (PAINS) filter and were synthetically feasible were synthesized in 3 steps using cheap and readily available reagents. The molecules were in vitro evaluated against Bcl-2-Jurkat, A-431 cancerous cell lines and ARPE-19 cell lines. Molecular Dynamics (MD) simulation studies were performed to analyse conformational changes induced by ligand 32 in Bcl-2. Flow cytometry analysis of compound 32 treated Bcl-2 cells was done to check apoptosis. Results: The molecules exhibited appreciable interactions with Bcl-2 and were having acceptable drug like properties as tested in silico. The multi step synthesis yielded 23 skeletally diverse thiazole-based molecules in up to 80% yield. The molecules simultaneously inhibited Bcl-2 Jurkat cells in vitro without causing detectable toxicity to normal cells (ARPE-19 cells). Among them molecules 32, 50, 53, 57 and 59 showed considerable activities against Bcl-2 Jurkat and A-431cell lines at concentrations ranging from 32–46 μM and 34–52 μM, respectively. The standard doxorubicin exhibited IC50 in Bcl-2 Jurkat and A-431cell lines at 45.87 μM and 42.37 μM, respectively. The molecule 32, almost equipotent in both the cell lines was subjected to molecular dynamics (MD) simulation with Bcl-2 protein (4IEH). It was shown that 32 interacted with protein majorly via hydrophobic interactions and few H-bonding interactions. Fluorescence-activated cell sorting (FACS) analysis established that molecule is dragging cancerous cells towards apoptosis. Discussion and conclusion: The chemical intuition was checked by computation coupled with biological results confirmed that thiazole-based hits have the potential to be developed downstream into potent and safer leads against antiapoptotic Bcl-2 cells.
- Anuradha,Patel, Sagarkumar,Patle, Rajkumar,Parameswaran, Preethi,Jain, Alok,Shard, Amit
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- Direct, Microwave-Assisted Synthesis of Isothiocyanates
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A microwave-assisted desulfuration of readily available dithiocarbamates, formed in situ from primary amines, leading to target isothiocyanates has been developed. This efficient protocol provides a rapid, environmentally benign route to aliphatic and aromatic isothiocyanates.
- Janczewski, ?ukasz,Gajda, Anna,Gajda, Tadeusz
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supporting information
p. 2528 - 2532
(2019/04/03)
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- Synthesis of thiocarbamoyl fluorides and isothiocyanates using CF3SiMe3 and elemental sulfur or AgSCF3 and KBr with amines
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Reactions of thiocarbonyl fluoride derived from cheap, readily available, and widely used CF3SiMe3, elemental sulfur, and KF with secondary amines and primary amines at room temperature in THF provided a wide variety of thiocarbamoyl fluorides and isothiocyanates in moderate to excellent yields, respectively. The two reactions show broad substrate scope and good functional group tolerance. Moreover, AgSCF3 reacts with secondary/primary amines under KBr at room temperature, affording quantitative thiocarbamoyl fluorides/isothiocyanates, which feature late-stage application.
- Zhen, Long,Fan, Hui,Wang, Xiaoji,Jiang, Liqin
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supporting information
p. 2106 - 2110
(2019/03/26)
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- Design, Synthesis, and Biological Evaluation of 6-Substituted Thieno[3,2- d]pyrimidine Analogues as Dual Epidermal Growth Factor Receptor Kinase and Microtubule Inhibitors
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The clinical evidence for the success of tyrosine kinase inhibitors in combination with microtubule-targeting agents prompted us to design and develop single agents that possess both epidermal growth factor receptor (EGFR) kinase and tubulin polymerization inhibitory properties. A series of 6-aryl/heteroaryl-4-(3′,4′,5′-trimethoxyanilino)thieno[3,2-d]pyrimidine derivatives were discovered as novel dual tubulin polymerization and EGFR kinase inhibitors. The 4-(3′,4′,5′-trimethoxyanilino)-6-(p-tolyl)thieno[3,2-d]pyrimidine derivative 6g was the most potent compound of the series as an antiproliferative agent, with half-maximal inhibitory concentration (IC50) values in the single- or double-digit nanomolar range. Compound 6g bound to tubulin in the colchicine site and inhibited tubulin assembly with an IC50 value of 0.71 μM, and 6g inhibited EGFR activity with an IC50 value of 30 nM. Our data suggested that the excellent in vitro and in vivo profile of 6g may be derived from its dual inhibition of tubulin polymerization and EGFR kinase.
- Romagnoli, Romeo,Prencipe, Filippo,Oliva, Paola,Baraldi, Stefania,Baraldi, Pier Giovanni,Schiaffino Ortega, Santiago,Chayah, Mariem,Kimatrai Salvador, Maria,Lopez-Cara, Luisa Carlota,Brancale, Andrea,Ferla, Salvatore,Hamel, Ernest,Ronca, Roberto,Bortolozzi, Roberta,Mariotto, Elena,Mattiuzzo, Elena,Viola, Giampietro
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supporting information
p. 1274 - 1290
(2019/01/30)
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- Synthesis of 2-substituted tetrahydroisoquinolin-6-ols: Potential scaffolds for estrogen receptor modulation and/or microtubule degradation
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6-Methoxytetrahydroisoquinoline hydrochloride was converted into four small libraries of substituted ureas, thioureas, sulfonamides and N-aryls, using the tetrahydroisoquinoline nitrogen as the scaffold-linking atom. Some of the compounds were evaluated for their ability to inhibit cell proliferation using the MCF7 (invasive ductal carcinoma) cell line.
- Mabank, Tanya,Alexandre, Kabamba B.,Pelly, Stephen C.,Green, Ivan R.,van Otterlo, Willem A.L.
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p. 245 - 279
(2020/02/13)
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- Na2S2O8-mediated efficient synthesis of isothiocyanates from primary amines in water
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We have developed two green, practical, and efficient procedures, including a one-pot one, to synthesize isothiocyanates from amines and carbon disulfide via desulfurization with sodium persulfate. Water is used as the solvent. Basic conditions are necessary for good chemoselectivity for isothiocyanates. Structurally diverse linear and branched alkyl amines and aryl amines are readily converted to isothiocyanates by the two procedures in satisfactory yields. Halogens, benzylic C-H bonds, methylthio, nitro, ester, alkenyl, electron-rich or -deficient (hetero)aryls, acetylenyl, and even phenolic and alcoholic hydroxyls are well tolerated. The one-pot procedure in water can also be used to realize the preparation of chiral isothiocyanates from chiral amines, and the modification of bioactive structures with free amino groups. In large-scale preparation, simple and practical purification procedures independent of column chromatography are developed.
- Fu, Zhicheng,Yuan, Wenhao,Chen, Ning,Yang, Zhanhui,Xu, Jiaxi
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supporting information
p. 4484 - 4491
(2018/10/17)
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- Design and discovery of quinazoline- and thiourea-containing sorafenib analogs as EGFR and VEGFR-2 dual TK inhibitors
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Both EGFR and VEGFR-2 play a critical role in tumor growth, angiogenesis and metastasis, and targeting EGFR and VEGFR-2 simultaneously represents a promising approach to cancer treatment. In this work, a series of novel quinazoline- and thiourea-containing sorafenib analogs (10a–v) were designed and synthesized as EGFR and VEGFR-2 dual TK inhibitors. Their in vitro enzymatic inhibitory activities against EGFR and VEGFR-2, and antiproliferative activities against HCT-116, MCF-7 and B16 cell lines were evaluated and described. Most of the compounds showed potent activities against both cell lines and TK kinases. Compounds 10b and 10q which exhibited the most potent inhibitory activities against EGFR (IC50 = 0.02 μM and 0.01 μM, respectively), VEGFR-2 (IC50 = 0.05 μM and 0.08 μM, respectively), and good antiproliferative activities, also displayed competitive anti-tumor activities than sorafenib in vivo by B16 melanoma xenograft model test.
- Sun, Shaofeng,Zhang, Jingwen,Wang, Ningning,Kong, Xiangkai,Fu, Fenghua,Wang, Hongbo,Yao, Jianwen
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- One-pot three-component tandem reaction: Synthesis of aryl/alkyl cyanamides libraries and their further conversion into tetrazole derivatives
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We have developed methodology for the synthesis of aryl/alkyl cyanamides from amines in one-pot four steps reaction using cheap, readily available and air stable copper source as catalyst under mild reaction conditions. We have also studied the application of cyanamides. In this connection, we could construct aryl tetrazolamine from cyanamides using click reaction.
- Mandapati, Usharani,Mandapati, Pavan,Pinapati, Srinivasarao,Tamminana, Ramana,Rudraraju, Rameshraju
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supporting information
p. 500 - 510
(2018/02/06)
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- Design and discovery of thioether and nicotinamide containing sorafenib analogues as multikinase inhibitors targeting B-Raf, B-RafV600E and VEGFR-2
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New sorafenib derivatives containing thioether and nicotinamide moiety were designed and synthesized as B-Raf, B-RafV600E and VEGFR-2 multikinase inhibitors. Their in vitro enzymatic inhibitory activities against B-Raf, B-RafV600E and VEGFR-2 and their antiproliferative activities against HCT-116 and B16BL6 cell lines were evaluated and described. Most of the compounds showed potent activities against both cell lines and specific kinases. Compounds a1, b1 and c4, which exhibited the most potent inhibitory activities against B-Raf with IC50 of 21 nM, 27 nM and 17 nM, B-RafV600E with IC50 of 29 nM, 28 nM and 16 nM, VEGFR-2 with IC50 of 84 nM, 46 nM and 63 nM, respectively, and good antiproliferative activities, also demonstrated competitive antiangiogenic activities to sorafenib in in vitro HUVEC tube formation assay.
- Sun, Shaofeng,He, Zuopeng,Huang, Mindong,Wang, Ningning,He, Zongzhong,Kong, Xiangkai,Yao, Jianwen
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p. 2381 - 2391
(2018/04/11)
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- Thiazolyl-thiadiazines as Beta Site Amyloid Precursor Protein Cleaving Enzyme-1 (BACE-1) Inhibitors and Anti-inflammatory Agents: Multitarget-Directed Ligands for the Efficient Management of Alzheimer's Disease
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Alzheimer's disease (AD) is associated with multiple neuropathological events including β-site amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibition and neuronal inflammation, ensuing degeneracy, and death to neuronal cells. Targeting such a complex disease via a single target directed treatment was found to be inefficacious. Hence, with an intention to incorporate multiple therapeutic effects within a single molecule, multitarget-directed ligands (MTDLs) have been evolved. Herein, for the first time, we report the discovery of novel thiazolyl-thiadiazines that can serve as MTDLs as evident from the in vitro and in vivo studies. These MTDLs exhibited BACE-1 inhibition down to micromolar range, and results from the in vivo studies demonstrated efficient anti-inflammatory activity with inherent gastrointestinal safety. Moreover, compound 6d unveiled noteworthy antioxidant, antiamyloid, neuroprotective, and antiamnesic properties. Overall, results of the present study manifest the potential outcome of thiazolyl-thiadiazines for AD treatment.
- Sagar, Sneha R.,Singh, Devendra Pratap,Panchal, Nirupa B.,Das, Rajesh D.,Pandya, Dhaivat H.,Sudarsanam, Vasudevan,Nivsarkar, Manish,Vasu, Kamala K.
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p. 1663 - 1679
(2018/05/14)
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- Synthesis and nematicidal activity of piperazinedione derivatives based on the natural product Barettin
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Nematodes are serious constraints of crop production worldwide. However, the traditional nematicides suffer from the side-effects, including environmental and human toxicity. Herein, more than 70 novel piperazinedione derivatives based on the natural product Barettin were synthesized and evaluated against the root-knot nematode Meloidogyne incognita (M. incognita). While most of synthesized compounds exhibited certain nematicidal activity at high concentration, the best one showed a nematicidal activity of 75% at 2.4 μmol/L.
- Sun, Haiyang,Li, Hui,Wang, Jiayi,Song, Gonghua
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p. 977 - 980
(2017/11/16)
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- Pyrazolone amide antifungal drug, and preparation method and application thereof
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The invention discloses a pyrazolone amide antifungal drug or its pharmaceutically acceptable salt. The structure of the compound is represented by general formula I shown in the description. In the general formula I, X is O or S; R1 is hydrogen, or a monosubstituent or a polysubstituent positioned at any position of a phenyl ring; R2 is hydrogen, a substituted or unsubstituted aromatic ring or cycloaliphatic ring, or a lower acyl group; and one of R3 and R4 is an amino group, and the remaining one is carbonyl oxygen. The invention discloses a preparation method of the compound, and an application of the compound in the preparation of an antifungal drug. Results of in-vitro antifungal activity experiments show that most of the compounds represented by general formula show have good antifungal activity characteristics, and have better antifungal activity on fungi comprising Candida albicans, fluconazole-resistant Candida albicans, Cryptococcus neoformans and Candida glabrata than a positive drug fluconazole.
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Paragraph 0065; 0066; 0068; 0069
(2018/09/12)
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- p-Aromatic Isothiocyanates: Synthesis and Anti Plant Pathogen Activity
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In this study, a series of p-aromatic isothiocyanates are prepared by reacting p-aromatic amines with carbon disulphide and further treating with molecular iodine to yield corresponding isothiocyanate derivatives. The structures of newly synthesized compounds are confirmed by IR, NMR, and MS data. Activity of the products against plant pathogenic fungi and bacteria is tested and the structure-activity relationship is approached. p-Nitrophenyl isothiocyanate most efficiently inhibits Rhizoctonia solani and Erwinia carotovora. The order of seven aromatic isothiocyanates antifungicidal activity is following: p-nitrophenyl > p-methoxyphenyl > p-chlorophenyl > p-methylphenyl > p-ethylphenyl > phenyl > p-fluorophenyl. For antibacterial activity, the order was p-nitrophenyl > p-chlorophenyl > p-methylphenyl > p-ethylphenyl > p-fluorophenyl > phenyl > p-methoxyphenyl. The present study indicates that some of the compounds exhibit promising antimicrobial activity and can be used as an alternative to the traditional synthetic fungicides for controlling R. solani and E. carotovora.
- Tang,Niu,Wang,Huo,Li,Luo,Cao
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p. 1252 - 1257
(2018/08/16)
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- N,N'-bis-substituted aryl thiourea derivatives and synthetic method and application thereof
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The invention discloses N,N'-bis-substituted aryl thiourea derivatives which are a series of compounds simultaneously containing various substituted aromatic ring structures and asymmetric substituted thiourea structures and are all novel structural compounds which are not reported in the literature. The biological activity test analysis of all the target compounds includes determination of DPPH antioxidant activity and antiviral activity. Results indicate that, in general, the designed and synthesized compounds are novel in structures and have the antioxidant activity and the antiviral activity revealed for the first time. In addition, the unknown biological activity is not fully elucidated, and thus the compounds are expected to provide a certain material basis for further research and development of new drugs.
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Paragraph 0080; 0089; 0090
(2017/04/26)
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- A block containing nicotinamide diphenyl thiourea compound and its salt preparation method and use of
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The invention relates to a diphenyl thiourea compound containing niacinamide building blocks and salt of the diphenyl thiourea compound. The chemical structure of the diphenyl thiourea compound is as shown in the description. The diphenyl thiourea compound and the salt, pharmaceutically acceptable, of the diphenyl thiourea compound have inhibiting effects on various tumour cell strains and can serve as effective components for preparing tumour treatment medicine.
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Paragraph 0085; 0086; 0094
(2017/08/02)
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- The structure of the amine-containing thiourea compound and its preparation method and application
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A disclosed thiourea compounds containing an arylamine structure comprises compounds of a general formula I and pharmaceutically acceptable salts. In the general formula I shown in the specification, R1 is selected from H, C1-C8 alkyl, halogens, -CF3, -OCF3, -NO2, -CN, R2O-, -SO2NH2, -NHSO2R3, -NR4R5, -CONR6R7, -COOR8, R9CO- and disubstituted and trisubstituted combinations thereof, R2, R3, R4, R5, R6, R7, R8 and R9 are respectively H or C1-C8 alkyl, L is selected from -NHR10, -NHOR11, -NR12R13, pyrrolidin-1-yl, 4-piperidyl and (4-methyl-1-piperazinyl)methylene, and R10, R11, R12 and R13 are respectively H, C1-C8 alkyl, cycloalkyl or aryl. The compounds have inhibiting effect on multiple tumor cell strains.
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Paragraph 0076; 0077; 0078; 0079; 0087
(2017/08/08)
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- Alkali-free green synthetic isothiocyanate method
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The invention discloses an alkali-free green synthetic method for isothiocyanate, and relates to the field of organic chemical industry. The method includes the steps: (1) adding solvents into carbon sulfide reagents and primary amine serving as raw materials, performing organic reaction at the temperature of 100-150 DEG C for 10-30 hours; (2) cooling and spin-drying the raw materials after reaction, adding dichloromethane, extracting and separating organic phases by 10% of dilute hydrochloride acid, washing the organic phases, combining the organic phases into an organic layer, washing the organic layer with saturated salt water, drying the organic layer by anhydrous Na2SO4, and performing column chromatographic separation to obtain the isothiocyanate. The molar ratio of the carbon sulfide reagents to the primary amine is 1:1.2-3. Compared with a preparation method in the prior art, the method has the advantages that only heating reaction needs to be performed in the solvents, additional alkali is omitted, and the method is greener and more environmentally friendly and has better application values.
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Paragraph 0024; 0025; 0026; 0042; 0043; 0044; 0045-0047
(2017/08/26)
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- Synthesis and antimicrobial activity of some new 1,2,4-trizoles
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A series of 1,2,4-triazole derivatives were synthesized using appropriate synthetic route and structures were confirmed by IR,1H NMR and elemental analysis. All the synthesized compounds (6a-6h and 7a-7h) were evaluated for antimicrobial activity by determining their minimum inhibitory concentrations (MICs) against a panel of Gram-positive, Gram-negative bacteria and fungi. Most of the compounds showed significant antimicrobial activity against Gram-positive bacteria viz. S. aureus, B. subtilis, Gram-negative bacteria viz. E. coli, P. aerugenosa and fungi viz. C. albicans, A. niger. Some of the compounds showed better antibacterial activities against Gram-positive bacteria compared to Gram-negative bacteria. Compounds 7g, 6g, 6a exhibited good MICs against Gram-positive bacteria and 7f showed better MICs against Gram-negative bacteria compared to reference norfloxacin. Compounds 7f and 7d exhibited MICs which is equipotent to the reference drug ketoconazole.
- Jain, Rakesh Kumar,Mishra, Vikash Kumar,Kashaw, Varsha
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p. 1317 - 1322
(2017/05/02)
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- Synthesis and biological evaluation of terminal functionalized thiourea-containing dipeptides as antitumor agents
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A series of antitumor agents based on terminal functionalized dipeptide derivatives containing the thiourea moiety were synthesized and evaluated for antiproliferative activity using a panel of cancer cell lines, and the effects and mechanism of apoptosis induction were determined. These compounds exhibited significant selectivity to different cancer cell lines with IC50 values at micromolar concentrations. In particular, compound I-11 appeared to be the most potent compound, with an IC50 = 4.85 ± 1.44 μM against the NCI-H460 cell line, at least partly, by the induction of apoptosis. Mechanistically, compound I-11 induced the activation of caspase-12 and CHOP, which triggered apoptotic signalling via the ROS-dependent endoplasmic reticulum pathway and arrested the cell cycle at the S phase. Thus, we concluded that dipeptide derivatives containing the thiourea moiety terminally functionalized by electron-withdrawing substituents may be potential antitumor agents for further investigation.
- Huang, Ri-Zhen,Zhang, Bin,Huang, Xiao-Chao,Liang, Gui-Bin,Qin, Jian-Mei,Pan, Ying-Ming,Liao, Zhi-Xin,Wang, Heng-Shan
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p. 8866 - 8878
(2017/02/10)
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- Reaction of Thiocarbonyl Fluoride Generated from Difluorocarbene with Amines
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The reaction of thiocarbonyl fluoride, generated from difluorocarbene, with various amines under mild conditions is described. Secondary amines, primary amines, and o-phenylenediamines are converted to thiocarbamoyl fluorides, isothiocyanates, and difluoromethylthiolated heterocycles, respectively. Thiocarbamoyl fluorides were further transformed into trifluoromethylated amines by using a one-pot process. Thiocarbonyl fluoride is generated in situ and is rapidly fully converted in one pot under mild conditions; therefore, no special safety precautions are needed.
- Yu, Jiao,Lin, Jin-Hong,Xiao, Ji-Chang
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supporting information
p. 16669 - 16673
(2017/12/07)
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- N-Aryl-N’-ethyleneaminothioureas effectively inhibit acetylcholinesterase 1 from disease-transmitting mosquitoes
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Vector control of disease-transmitting mosquitoes by insecticides has a central role in reducing the number of parasitic- and viral infection cases. The currently used insecticides are efficient, but safety concerns and the development of insecticide-resistant mosquito strains warrant the search for alternative compound classes for vector control. Here, we have designed and synthesized thiourea-based compounds as non-covalent inhibitors of acetylcholinesterase 1 (AChE1) from the mosquitoes Anopheles gambiae (An. gambiae) and Aedes aegypti (Ae. aegypti), as well as a naturally occurring resistant-conferring mutant. The N-aryl-N’-ethyleneaminothioureas proved to be inhibitors of AChE1; the most efficient one showed submicromolar potency. Importantly, the inhibitors exhibited selectivity over the human AChE (hAChE), which is desirable for new insecticides. The structure-activity relationship (SAR) analysis of the thioureas revealed that small changes in the chemical structure had a large effect on inhibition capacity. The thioureas showed to have different SAR when inhibiting AChE1 and hAChE, respectively, enabling an investigation of structure-selectivity relationships. Furthermore, insecticidal activity was demonstrated using adult and larvae An. gambiae and Ae. aegypti mosquitoes.
- Knutsson, Sofie,Kindahl, Tomas,Engdahl, Cecilia,Nikjoo, Dariush,Forsgren, Nina,Kitur, Stanley,Ekstr?m, Fredrik,Kamau, Luna,Linusson, Anna
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p. 415 - 427
(2017/04/24)
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- Copper promoted desulfurization towards the synthesis of isothiocyanates
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The cheap, readily available and air stable catalyst was used as the desulfurization agent for the conversion of aniline to isothiocyanates in one pot two step reaction under mild reaction conditions.
- Mandapati, UshaRani,Pinapati, Srinivasarao,Rudraraju, RameshRaju
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p. 125 - 128
(2016/12/26)
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- Synthesis and nematicidal activities of 1,2,3-benzotriazin-4-one derivatives containing thiourea and acylthiourea against Meloidogyne incognita
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Two series of novel 1,2,3-benzotriazin-4-one derivatives containing thiourea and acylthiourea were designed and synthesized. The bioassay results showed that most of the test compounds showed good nematicidal activity against M. incognita at the concentration of 10.0?mg?L?1 in vivo. The compounds A13, A17 and B3 showed excellent nematicidal activity on the second stage juveniles of the root-knot nematode with the inhibition rate of 51.3%, 58.3% and 51.3% at the concentration of 1.0?mg?L?1 respectively. It suggested that the structure of 1,2,3-benzotriazin-4-one derivatives containing thiourea and acylthiourea could be optimized further.
- Chang, Yaning,Zhang, Jingwei,Chen, Xiulei,Li, Zhong,Xu, Xiaoyong
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p. 2641 - 2644
(2017/05/10)
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- A novel one-pot synthesis of isothiocyanates and cyanamides from dithiocarbamate salts using environmentally benign reagent tetrapropylammonium tribromide
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A highly efficient and simple protocol for the synthesis of isothiocyanates and cyanamides from their respective amines in the presence of a mild, efficient, and non-toxic reagent tetrapropylammonium tribromide is described. High environmental acceptability of the reagents, cost effectiveness and high yields are the important attributes of this methodology.
- Kuotsu, Neivotsonuo Bernadette,Jamir, Latonglila,Phucho, Tovishe,Sinha, Upasana Bora
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p. 832 - 841
(2018/01/17)
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- Double three bromo 1,3-di-pyridine salt-based propane and its preparation method, method of use, recovery method and application
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The invention discloses a double tribromo 1,3-bipyridine onium salt dimethylmethane, and a preparation method, an application method, a recovery method and application thereof. The preparation method comprises the following steps: dissolving 1,3-bipyridine onium salt dimethylmethane by using water, and then adding potassium bromide; adding potassium peroxymonosulfate sulfate compound brine solution to prepare a clear solution after dissolving potassium bromide, and then stirring and reacting at -10 to 0 DEG C until solid is separated out; separating out solid, so as to obtain the double tribromo 1,3-bipyridine onium salt dimethylmethane. The product can be used for preparing isothiocyanate, aromatic thiourea or acetanilide. The preparation method disclosed by the invention is mild in condition, and simple to operate the reaction process, and raw materials are easily available. The double tribromo 1,3-bipyridine onium salt dimethylmethane not only can be used as a brominating reagent, but also can be used as organic synthesis intermediates, meanwhile, the reaction efficiency is improved, and the double tribromo 1,3-bipyridine onium salt dimethylmethane is convenient to recover and can be recycled.
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Paragraph 0080; 0081; 0090; 0091
(2016/10/07)
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- NOVEL BENZIMIDAZOLE BASED EGFR INHIBITORS
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The present invention disclosed a novel EGFR inhibitor compound of formula (I), process for preparation thereof and methods of treating abnormal cell growth in mammals by administering the compounds of formula (I). Wherein, R= -H, 3-CH3, 4-NO2, 4-Cl, 2-CH3, 4-CH3, 4-Br, 4-F R1= -H, -4-OCH3, -4-NO2,-2-NO2, -4-Cl, -2,4,6-CH3, -4-CH3, -2-F,4-Br, -4-CF3, -4-S-CH3, -4-Cl,-3-CF3, -3-S-CH3, -3,5-CF3, -2-S-CH3, -3-CF3,-4-OCF3, -Si-(CH3)3, -Si-(C2H5)3, (CH3)2-Si- C2H5.
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Page/Page column 12
(2016/06/15)
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- Synthesis of 4-phenylthieno[2, 3-e][1, 2, 4]triazolo[4, 3-a]pyrimidine-5 (4H)-one derivatives and evaluation of their anti-inflammatory activity
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A series of 4-phenylthieno[2, 3-e][1, 2, 4]triazolo[4, 3-a]pyrimidine-5 (4H)-ones (5a-p) with triazole or other heterocyclic substituents (6-11) was synthesized and the compounds were evaluated for their anti-inflammatory activity using the xylene-induced ear-edema test. Pharmacological analyses showed that the compound 4- (4-chlorophenyl)thieno[2, 3-e][1, 2, 4]triazolo[4, 3-a]pyrimidine- 5 (4H)-one (5m) exhibited the greatest anti-inflammatory activity (50.48% inhibition, 30 min after intraperitoneal administration) and was more potent than the reference drug, indomethacin. The peak activity of 5m was observed 4 h after oral administration, and it showed a higher anti-inflammatory activity than indomethacin did at a dose of 100 mg/kg.
- Pan, Fu-Jun,Wang, Shi-Ben,Liu, Da-Chuan,Gong, Guo-Hua,Quan, Zhe-Shan
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p. 141 - 148
(2016/03/12)
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- An efficient methodology for the synthesis of thioureas from amine mediated by a cobalt source
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The cheap, readily available and air stable cobalt catalyst was used as the desulfurization agent for the conversion of aniline to thioureas in one pot three step reaction under mild reaction conditions. The reactions are rapid and facile and accomplished at room temperature.
- Seelam, Mohan,Shaikh, Baji Vali,Tamminana, Ramana,Kammela, Prasada Rao
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supporting information
p. 5297 - 5300
(2016/11/11)
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- Design, synthesis and structure-activity relationships of novel diaryl urea derivatives as potential EGFR inhibitors
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Two novel series of diaryl urea derivatives 5a-i and 13a-l were synthesized and evaluated for their cytotoxicity against H-460, HT-29, A549, and MDA-MB-231 cancer cell lines in vitro. Therein, 4-aminoquinazolinyl-diaryl urea derivatives 5a-i demonstrated significant activity, and seven of them are more active than sorafenib, with IC50 values ranging from 0.089 to 5.46 μM. Especially, compound 5a exhibited the most active potency both in cellular (IC50 = 0.15, 0.089, 0.36, and 0.75 μM, respectively) and enzymatic assay (IC50 = 56 nM against EGFR), representing a promising lead for further optimization.
- Jiang, Nan,Bu, Yanxin,Wang, Yu,Nie, Minhua,Zhang, Dajun,Zhai, Xin
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- Cobalt mediated by desulfurization toward the synthesis of isothiocyanates
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A highly efficient and simple protocol for the construction of aromatic and aliphatic isothiocyanates from their respective amines in the presence of cheap, readily available, and air-stable cobalt catalyst is described. All reactions were carried out under optimized reaction conditions and gave target products in good to excellent yields within shorter reaction time.
- Seelam, Mohan,Shaik, Bajivali,Kammela, Prasada Rao
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supporting information
p. 1759 - 1765
(2016/10/31)
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- Enantioselective synthesis of 3,5-disubstituted thiohydantoins and hydantoins
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A mild method to convert optically pure amino acid thiourea and urea derivatives to thiohydantoins and hydantoins, respectively, is described. It provides an efficient way to realize enantioselective synthesis of thiohydantoins and hydantoins with good to high isolated yields and enantiomeric purities. We found that the enantiomeric purities were highly dependent on the reaction conditions including bases, solvents, and temperature.
- Chen, Yu,Su, Li,Yang, Xinying,Pan, Wenyan,Fang, Hao
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p. 9234 - 9239
(2015/11/27)
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- Pyrazolopyrimidines: Potent Inhibitors Targeting the Capsid of Rhino- and Enteroviruses
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There are currently no drugs available for the treatment of enterovirus (EV)-induced acute and chronic diseases such as the common cold, meningitis, encephalitis, pneumonia, and myocarditis with or without consecutive dilated cardiomyopathy. Here, we report the discovery and characterization of pyrazolopyrimidines, a well-tolerated and potent class of novel EV inhibitors. The compounds inhibit the replication of a broad spectrum of EV in vitro with IC50 values between 0.04 and 0.64 μM for viruses resistant to pleconaril, a known capsid-binding inhibitor, without affecting cytochrome P450 enzyme activity. Using virological and genetics methods, the viral capsid was identified as the target of the most promising, orally bioavailable compound 3-(4-trifluoromethylphenyl)amino-6-phenylpyrazolo[3,4-d]pyrimidine-4-amine (OBR-5-340). Its prophylactic as well as therapeutic application was proved for coxsackievirus B3-induced chronic myocarditis in mice. The favorable pharmacokinetic, toxicological, and pharmacodynamics profile in mice renders OBR-5-340 a highly promising drug candidate, and the regulatory nonclinical program is ongoing. Curing the common cold! A cluster of pyrazolopyrimidines with potent broad-spectrum activity against enteroviruses was discovered. Extensive structure-property relationship analyses led to the identification of 3-(4-trifluoromethyl-phenyl)amino-6-phenylpyrazolo[3,4-d]pyrimidine-4-amine, shown to be a blocker of the viral capsid protein, as a lead compound for drug development with favorable physicochemical, pharmacokinetic, and toxicological properties.
- Makarov, Vadim A.,Braun, Heike,Richter, Martina,Riabova, Olga B.,Kirchmair, Johannes,Kazakova, Elena S.,Seidel, Nora,Wutzler, Peter,Schmidtke, Michaela
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supporting information
p. 1629 - 1634
(2015/10/06)
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- Design, synthesis and in vitro evaluation of novel ursolic acid derivatives as potential anticancer agents
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A series of novel ursolic acid (UA) derivatives modified at the C-3 and the C-28 positions were designed and synthesized in an attempt to develop potential antitumor agents. The in vitro cytotoxicity were evaluated against five cancer cell lines (MGC-803, HCT-116, T24, HepG2 and A549 cell lines) and a normal cell (HL-7702) by MTT assay. The screening results indicated that some of these target compounds displayed moderate to high levels of antiproliferative activities compared with ursolic acid and 5-fluorouracil (5-FU), and exhibited much lower cytotoxicity than 5-FU, indicating that the targeted compounds had selective and significant effect on the cell lines. The induction of apoptosis and affects on the cell cycle distribution of compound 6r were investigated by acridine orange/ethidium bromide staining, Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining and flow cytometry, which revealed that the antitumor activity of 6r was possibly achieved through the induction of cell apoptosis by G1 cell-cycle arrest. Western blot and qRT-PCR (quantitative real-time PCR) experiments demonstrated that compound 6r may induce apoptosis through both of intrinsic and extrinsic apoptosis pathway.
- Hua, Shi-Xian,Huang, Ri-Zhen,Ye, Man-Yi,Pan, Ying-Ming,Yao, Gui-Yang,Zhang, Ye,Wang, Heng-Shan
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p. 435 - 452
(2015/04/14)
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