cas 1985-12-2, 4-BROMOPHENYL ISOTHIOCYANATE

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Facile synthesis of 1-(4-bromophenyl)-1H-tetrazol-5-amine and related amide derivatives
An efficient one-pot synthesis of 1-(4-bromophenyl)-1H-tetrazol-5-amine was performed using 4-bromoaniline as the starting material. A novel and widely applicable amidation procedure was then employed, whereby 1-(4-bromophenyl)-1H-tetrazol-5-amine was acylated with different acyl chlorides in the presence of lithium bis(trimethylsilyl)amide as catalyst, for the high-yield synthesis of [1-(4-bromophenyl)-1H-tetrazol-5-yl]amide derivatives.
Yang, Hao,Ouyang, Yifan,Sun, Yutong,Wang, Zhe,Zhu, Xuanli,Tan, Xiaoli,Wang, Hao,Hong, Wei
p. 581 - 585
(2017)
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Transition-metal complexes of N,N′-di(4-bromophenyl)-4-hydroxycoumarin-3-carboximidamide: synthesis, characterization, biological activities, ADMET and drug-likeness analysis
Coordination compounds of N,N’-di(4-bromophenyl)-4-hydroxycoumarin-3-carboximidamide (L1) were synthesized via the reaction of Cu (II), Co (II) and Zn (II) salts in molar ratio 1 : 1 in the presence of ammoniac as basic media. The Ligands and the complexes formed were characterized using FT-IR, UV–visible and fluorescence spectrophotometric analyses, mass spectrometry, elemental analyses and NMR spectroscopy. It was concluded that N,N’-di(4-bromophenyl)-4-hydroxycoumarin-3-carboximidamide (L1) coordinated as a mono ligand for all the complexes; it also coordinated via the –OH and –NH groups. The electrochemical behaviour of these compounds was determined by cyclic voltammetry. The synthesized compounds were screened for their antimicrobial and antioxidant activities. All the complexes except that of copper show good activities against the S. aureus and those of cobalt and zinc have very interesting diameters of inhibition but lower antioxidant activity than the ligand L1. Parameters drug-likeness and ADMET (Absorption, Distribution, Metabolism, and Excretion) properties have been calculated.
Belkhir-Talbi, Drifa,Ghemmit-Doulache, Naima,Terrachet-Bouaziz, Souhila,Makhloufi-Chebli, Malika,Rabahi, Amal,Ismaili, Lhassane,Silva, Artur M.S.
(2021/03/16)

Design, synthesis and biological evaluation of novel 2,4-disubstituted quinazoline derivatives targeting H1975 cells via EGFR-PI3K signaling pathway
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
(2021/07/28)

Discovery of quinazoline derivatives as a novel class of potent and in vivo efficacious LSD1 inhibitors by drug repurposing
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
(2021/08/19)

Tetrabutylammonium Iodide/I2 Mediated Convenient and Green Synthesis of Substituted Organic Isothiocyanates
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Srivastava, Nitin
p. 562 - 570
(2021/10/07)

NaOH-promoted one-pot aryl isothiocyanate synthesis under mild benchtop conditions
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
supporting information
p. 839 - 844
(2021/05/27)

A catalyst-free method for the synthesis of 1,4,2-dithiazoles from isothiocyanates and hydroxylamine triflic acid salts
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
supporting information
p. 6206 - 6209
(2021/07/28)

Synthesis of isothiocyanates using DMT/NMM/TsO? as a new desulfurization reagent
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
(2021/05/29)

N-Trifluoromethyl Hydrazines, Indoles and Their Derivatives
Reported herein is the first efficient strategy to synthesize a broad range of unsymmetrical N-CF3 hydrazines, which served as platform to unlock numerous currently inaccessible derivatives, such as tri- and tetra-substituted N-CF3 hydrazines, hydrazones, sulfonyl hydrazines, and valuable N-CF3 indoles. These compounds proved to be remarkably robust, being compatible with acids, bases, and a wide range of synthetic manipulations. The feasibility of RN(CF3)-NH2 to function as a directing group in C?H functionalization is also showcased.
Bouayad-Gervais, Samir,Scattolin, Thomas,Schoenebeck, Franziska
supporting information
p. 11908 - 11912
(2020/05/18)

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
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
(2020/06/29)

Synthesis of thiocarbamoyl fluorides and isothiocyanates using amines with CF3SO2Cl
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
p. 12374 - 12381
(2020/11/10)

Synthesis and biological evaluation of innovative thiourea derivatives as PHGDH inhibitors
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
p. 3873 - 3886
(2020/05/29)

Thiosemicarbazone-based lead optimization to discover high-efficiency and low-toxicity anti-gastric cancer agents
In this paper, a series of thiosemicarbazone derivatives containing different aromatic heterocyclic groups were synthesized and the tridentate donor system of the lead compound was optimized. Most of the target compounds showed improved antiproliferative activity against MGC803 cells. SAR studies revealed that compound 5d displayed significant advantages in inhibition effect with an IC50 value of 0.031 μM, and better selectivity between cancer and normal cells than 3-AP and DpC (about 15- and 5-fold improved respectively). Besides, compound 5d showed selective antiproliferative activity in not only other cancer cells but also different gastric cancer cell lines. In-depth mechanism studies showed that compound 5d could induce mitochondria-related apoptosis which might be related to the elevation of intracellular ROS level, and cause cell cycle arrest at S phase. Moreover, 5d could evidently suppress the cell migration and invasion by blocking the EMT (epithelial–mesenchymal transition) process. Consequently, our studies provided a lead optimization strategy of thiosemicarbazone derivatives which would contribute to discover high-efficiency and low-toxicity agents for the treatment of gastric cancer.
Bo-Wang,He, Zhang-Xu,Li, Yi-Han,Liu, Hong-Min,Ma, Li-Ying,Ma, Qin,Tao, Yuan-Yuan,Wang, Hao-Jie,Wu, Hui-Pan,Zhang, Xin-Hui,Zhao, Bing
(2020/05/19)

Synthesis methods for isothiocyanate derivative
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; 0053; 0054; 0055; 0056

(2019/05/22)

A thiourea structure unit including shrinking amino aromatic compound and its preparation method and application (by machine translation)
The invention relates to the technical field of pharmaceutical chemistry, and in particular relates to a thiourea structure unit including shrinking amino aromatic compound and its preparation method and application. The present invention provides including shrinking amino thiourea structure unit of the aromatic heterocyclic compound with the gastric cancer cells through the inner metal ion chelating form stable complexes, thereby suppressing the MGC803 gastric cancer cell proliferation activity. The results of the embodiment of the display, and the compound 3 - AP compared with, the present invention provides including shrinking amino thiourea structure unit of the aromatic heterocyclic compound to stomach MGC803 has better proliferation inhibitory activity. (by machine translation)
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Paragraph 0119-0123; 0128-0132

(2019/07/10)

Direct, Microwave-Assisted Synthesis of Isothiocyanates
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
p. 2528 - 2532
(2019/04/03)

Synthesis of thiocarbamoyl fluorides and isothiocyanates using CF3SiMe3 and elemental sulfur or AgSCF3 and KBr with amines
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
supporting information
p. 2106 - 2110
(2019/03/26)

Synthesis and nematicidal activity of piperazinedione derivatives based on the natural product Barettin
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
p. 977 - 980
(2017/11/16)

Na2S2O8-mediated efficient synthesis of isothiocyanates from primary amines in water
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
p. 4484 - 4491
(2018/10/17)

N,N'-bis-substituted aryl thiourea derivatives and synthetic method and application thereof
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; 0093; 0094

(2017/04/26)

Synthesis and antimicrobial activity of some new 1,2,4-trizoles
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
p. 1317 - 1322
(2017/05/02)

Synthesis, structure-activity relationship and binding mode analysis of 4-thiazolidinone derivatives as novel inhibitors of human dihydroorotate dehydrogenase
A series of 4-thiazolidinone derivatives were synthesized and evaluated as novel human dihydroorotate dehydrogenase (hDHODH) inhibitors. Compounds 26 and 31 displayed IC50 values of 1.75 and 1.12 μM, respectively. The structure-activity relationship was summarized. Further binding mode analysis revealed that compound 31 could form a hydrogen bond with Tyr38 and a water-mediated hydrogen bond with Ala55, which may be necessary for maintaining the bioactivities of the compounds in this series. Further structural optimization of the para- or meta-position of the phenyl group at R will lead to the identification of more potent hDHODH inhibitors.
Zeng, Fanxun,Qi, Tiantian,Li, Chunyan,Li, Tingfang,Li, Honglin,Li, Shiliang,Zhu, Lili,Xu, Xiaoyong
p. 1297 - 1302
(2017/07/07)

A novel one-pot synthesis of isothiocyanates and cyanamides from dithiocarbamate salts using environmentally benign reagent tetrapropylammonium tribromide
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
p. 832 - 841
(2018/01/17)

Reaction of Thiocarbonyl Fluoride Generated from Difluorocarbene with Amines
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
supporting information
p. 16669 - 16673
(2017/12/07)

Isothiocyanation of amines using the Langlois reagent
The Langlois reagent was found to be effective for the isothiocyanation of primary amines in the presence of copper iodide and diethyl phosphonate.
Liao, Yan-Yan,Deng, Jian-Chao,Ke, Yan-Ping,Zhong, Xiao-Lin,Xu, Li,Tang, Ri-Yuan,Zheng, Wenxu
supporting information
p. 6073 - 6076
(2017/07/10)

Terminal functionalized thiourea-containing dipeptides as multidrug-resistance reversers that target 20S proteasome and cell proliferation
A series of inhibitors of 20S proteasome based on terminal functionalized dipeptide derivatives containing the thiourea moiety were synthesized and evaluated for inhibition of 20S proteasome and the effects of multidrug-resistance reversers. These compounds exhibited significant selectivity to the β5-subunit of the human 20S proteasome with IC50values at submicromolar concentrations. A docking study of the most active compound 6i revealed key interactions between 6i and the active site of the 20S proteasome in which the thiourea moiety and a nitro group were important for improving activity. In particular, compound 6i appeared to be the most potent compound against the NCI-H460 cell line, and displayed similar efficiency in drug-sensitive versus drug-resistant cancer cell lines, at least partly, by inhibition of the activity of 20S proteasome and induce apoptosis. In addition, 6i-induced apoptosis was significantly facilitated in NCI-H460/DOX cells that had been pretreated with inhibitors of P-gp. Mechanistically, compound 6i might trigger apoptotic signalling pathway. Thus, we conclude that dipeptide derivatives containing the thiourea moiety may be the potential inhibitors of proteasome with the ability to reverse multidrug resistance.
Qin, Jian-Mei,Huang, Ri-Zhen,Yao, Gui-Yang,Liao, Zhi-Xin,Pan, Ying-Ming,Wang, Heng-Shan
p. 259 - 269
(2016/12/02)

Integrated bioinformatics, computational and experimental methods to discover novel Raf/extracellular-signal regulated kinase (ERK) dual inhibitors against breast cancer cells
Beginning with our previously reported ERK inhibitor BL-EI001, we found Raf1 to be an important regulator in the ERK interactive network, and then we designed and synthesized a novel series of Raf1/ERK dual inhibitors against human breast cancers through integrative computational, synthetic and biological screening methods. Moreover, we found that compound 9d suppressed the proliferation of breast cancer cell lines and induced cellular apoptosis via a mitochondrial pathway with only partial dependence on Raf1 and ERK. Our results suggest that an integrative method including in silico design, chemical synthesis, biological screening and bioinformatics analysis could be an attractive strategy for the discovery of multi-target inhibitors against breast cancer.
Chen, Yin,Zheng, Yaxin,Jiang, Qinglin,Qin, Feifei,Zhang, Yonghui,Fu, Leilei,He, Gu
p. 997 - 1011
(2017/02/18)

Synthesis and evaluation of frentizole-based indolyl thiourea analogues as MAO/ABAD inhibitors for Alzheimer's disease treatment
Alzheimer's disease (AD) is a neurodegenerative disorder associated with an excessive accumulation of amyloid-beta peptide (Aβ). Based on the multifactorial nature of AD, preparation of multi-target-directed ligands presents a viable option to address more pathological events at one time. A novel class of asymmetrical disubstituted indolyl thioureas have been designed and synthesized to interact with monoamine oxidase (MAO) and/or amyloid-binding alcohol dehydrogenase (ABAD). The design combines the features of known MAO inhibitors scaffolds (e.g. rasagiline or ladostigil) and a frentizole moiety with potential to interact with ABAD. Evaluation against MAO identified several compounds that inhibited in the low to moderate micromolar range. The most promising compound (19) inhibited human MAO-A and MAO-B with IC50values of 6.34 μM and 0.30 μM, respectively. ABAD activity evaluation did not show any highly potent compound, but the compound series allowed identification of structural features to assist the future development of ABAD inhibitors. Finally, several of the compounds were found to be potent inhibitors of horseradish peroxidase (HRP), preventing the use of the Amplex Red assay to detect hydrogen peroxide produced by MAO, highlighting the need for serious precautions when using an enzyme-coupled assay.
Hroch, Lukas,Guest, Patrick,Benek, Ondrej,Soukup, Ondrej,Janockova, Jana,Dolezal, Rafael,Kuca, Kamil,Aitken, Laura,Smith, Terry K.,Gunn-Moore, Frank,Zala, Dominykas,Ramsay, Rona R.,Musilek, Kamil
p. 1143 - 1152
(2017/02/05)

Double three bromo 1,3-di-pyridine salt-based propane and its preparation method, method of use, recovery method and application
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 0075; 0076; 0105; 0106

(2016/10/07)

Synthesis of monosubstituted thioureas by vapour digestion and mechanochemical amination of thiocarbamoyl benzotriazoles
Thiocarbamoyl benzotriazoles, as safe and easy-to-handle isothiocyanate equivalents, were quantitatively converted to N-monosubstituted thioureas by vapour digestion synthesis under an ammonia atmosphere. This simple, but timely process provided a synthetic platform that enabled the "slow" amination reaction to be successfully transformed into a rapid one aided by mechanochemical milling. The ammonium chloride/sodium carbonate equimolar mixture allowed in situ formation of ammonia under ball-milling conditions. This novel and green approach yielded aromatic and aliphatic primary thioureas in near-quantitative isolated yields with workup entirely based on using only water. In addition, the molecular and crystal structures of selected polyaromatic primary thioureas were determined from the synchrotron powder diffraction data.
Dud, Mateja,Magdysyuk, Oxana V.,Margeti?, Davor,?trukil, Vjekoslav
p. 2666 - 2674
(2016/05/24)

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
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
p. 141 - 148
(2016/03/12)

Naphthyridine derivatives as a model system for potential lithium-sulfur energy-storage applications
Naphthyridines have been identified as structural elements in sulfurized polyacrylonitrile, which is a common electrode material in lithium-sulfur batteries. Some dibenzonaphthyridine derivatives with a fused dithiolo moiety were prepared as model compounds for battery studies. These heterocyclic systems were prepared via the corresponding diphenyldicarbamide intermediate. Followed by naphthyridione formation, stepwise installation of the dithiolane subunit occurred in a straightforward manner. In the solid state, the heteroaromatic system is completely planar and was thoroughly characterized. Initial battery cycling tests indicated a potential use of such structural motifs in sulfur-lithium systems.
Resch, Sebastian,Schneider, Anna-Rebekka,Beichler, Ronja,Spera, Marcelle B. M.,Fanous, Jean,Schollmeyer, Dieter,Waldvogel, Siegfried R.
supporting information
p. 933 - 937
(2015/02/19)

Design, synthesis, X-ray crystallographic analysis, and biological evaluation of thiazole derivatives as potent and selective inhibitors of human dihydroorotate dehydrogenase
Human dihydroorotate dehydrogenase (HsDHODH) is a flavin-dependent mitochondrial enzyme that has been certified as a potential therapeutic target for the treatment of rheumatoid arthritis and other autoimmune diseases. On the basis of lead compound 4, which was previously identified as potential HsDHODH inhibitor, a novel series of thiazole derivatives were designed and synthesized. The X-ray complex structures of the promising analogues 12 and 33 confirmed that these inhibitors bind at the putative ubiquinone binding tunnel and guided us to explore more potent inhibitors, such as compounds 44, 46, and 47 which showed double digit nanomolar activities of 26, 18, and 29 nM, respectively. Moreover, 44 presented considerable anti-inflammation effect in vivo and significantly alleviated foot swelling in a dose-dependent manner, which disclosed that thiazole-scaffold analogues can be developed into the drug candidates for the treatment of rheumatoid arthritis by suppressing the bioactivity of HsDHODH.
Zhu, Junsheng,Han, Le,Diao, Yanyan,Ren, Xiaoli,Xu, Minghao,Xu, Liuxin,Li, Shiliang,Li, Qiang,Dong, Dong,Huang, Jin,Liu, Xiaofeng,Zhao, Zhenjiang,Wang, Rui,Zhu, Lili,Xu, Yufang,Qian, Xuhong,Li, Honglin
p. 1123 - 1139
(2015/03/04)

Design, synthesis and in vitro evaluation of novel ursolic acid derivatives as potential anticancer agents
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
p. 435 - 452
(2015/04/14)

N-aryl-2-aminobenzimidazoles: Novel, efficacious, antimalarial lead compounds
From the phenotypic screening of the AstraZeneca corporate compound collection, N-aryl-2-aminobenzimidazoles have emerged as novel hits against the asexual blood stage of Plasmodium falciparum (Pf). Medicinal chemistry optimization of the potency against Pf and ADME properties resulted in the identification of 12 as a lead molecule. Compound 12 was efficacious in the P. berghei (Pb) model of malaria. This compound displayed an excellent pharmacokinetic profile with a long half-life (19 h) in rat blood. This profile led to an extended survival of animals for over 30 days following a dose of 50 mg/kg in the Pb malaria model. Compound 12 retains its potency against a panel of Pf isolates with known mechanisms of resistance. The fast killing observed in the in vitro parasite reduction ratio (PRR) assay coupled with the extended survival highlights the promise of this novel chemical class for the treatment of malaria.
Ramachandran, Sreekanth,Hameed P., Shahul,Srivastava, Abhishek,Shanbhag, Gajanan,Morayya, Sapna,Rautela, Nikhil,Awasthy, Disha,Kavanagh, Stefan,Bharath, Sowmya,Reddy, Jitendar,Panduga, Vijender,Prabhakar,Saralaya, Ramanatha,Nanduri, Robert,Raichurkar, Anandkumar,Menasinakai, Sreenivasaiah,Achar, Vijayashree,Jiménez-Díaz, María Belén,Martínez, María Santos,Angulo-Barturen, I?igo,Ferrer, Santiago,Sanz, Laura María,Gamo, Francisco Javier,Duffy, Sandra,Avery, Vicky M.,Waterson, David,Lee, Marcus C. S.,Coburn-Flynn, Olivia,Fidock, David A.,Iyer, Pravin S.,Narayanan, Shridhar,Hosagrahara, Vinayak,Sambandamurthy, Vasan K.
p. 6642 - 6652
(2014/10/15)

ISOTHIOCYNATES AND GLUCOSINOLATE COMPOUNDS AND ANTI-TUMOR COMPOSITIONS CONTAINING SAME
The present invention provides glucosinolate and isothiocyanate compounds and related methods for synthesizing these compounds and analogs. In certain embodiments, these glucosinolate and isothiocyanate compounds are useful and chemopreventive and or chemotherapeutic agents.
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Paragraph 0094; 0096; 0101

(2013/05/21)

Synthesis of new enantiopure thioureas derived from (S)-proline
Enantiopure thiourea derivatives, containing pyrrolidine ring, were prepared by the reaction of N-Boc-(S)-2-aminomethylpyrrolidine (6) with thioisocyanates 8.
Wroblewska, Aneta,Mloston, Grzegorz
p. 509 - 511
(2013/07/25)

N-ARYLTRIAZOLE COMPOUNDS AS LPAR ANTAGONISTS
Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of inflammatory diseases and disorders such as, for example, pulmonary fibrosis
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Page/Page column 82-83

(2014/01/09)

The rapid generation of isothiocyanates in flow
Isothiocyanates are versatile starting materials for a wide range of chemical reactions. However, their high nucleophilic susceptibility means they are best prepared and used immediately. We report here on a flow platform for the fast and efficient formation of isothiocyanates by the direct conversion of easily prepared chloroximes. To expedite this chemistry a flow insert cartridge containing two immobilised reagents is used to affect the chemical transformation which typically eliminates the requirements for any conventional work-up or purification of the reaction stream.
Baumann, Marcus,Baxendale, Ian R.
p. 1613 - 1619
(2013/10/22)

Synthesis of isothiocyanates by reaction of amines with phenyl chlorothionoformate via one-pot or two-step process
A facile and efficient synthesis of isothiocyanates from amines is described. This method involves the reaction of amines with phenyl chlorothionoformate in the presence of solid sodium hydroxide by either a one-pot process or a two-step approach. The one-pot process is useful for preparing alkyl and electron-rich aryl isothiocyanates, whereas the two-step approach is more versatile, working very well not only for alkyl and electron-rich aryl isothiocyanates, but also for highly electron-deficient aryl and heterocyclic isothiocyanates. Georg Thieme Verlag Stuttgart, New York.
Li, Zheng-Yi,Ma, Hong-Zhao,Han, Chen,Xi, Hai-Tao,Meng, Qi,Chen, Xin,Sun, Xiao-Qiang
p. 1667 - 1674
(2013/07/19)

Facile and versatile synthesis of alkyl and aryl isothiocyanates by using triphosgene and cosolvent
A mild and efficient method for the conversion of alkyl and aryl amines to isothiocyanates via dithiocarbamates has been developed using (CH 3)2CO-CS2 as co-solvent and triphosgene as dehydrosulfurization reagent. High yields, mild reaction conditions and excellent functional group compatibility make it become a versatile synthetic method for the preparation of isothiocyanates compared with reported methods. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]
Liu, Pengfei,Li, Chunyan,Zhang, Jingwei,Xu, Xiaoyong
p. 3342 - 3351
(2013/10/01)

Chloroarylation and thiocyanatoarylation of itaconic acid
Under conditions of Meerwein reaction and anionarylation the aryldiazonium salts and itaconic acid form 2-chloro(thiocyanato)-2-benzylbutanedioic acids as the chloro- and thiocyianatoarylation products. The reaction is not accompanied by the decarboxylati
Baranovskii,Petrushka,Fesak,Grishchuk
p. 325 - 328
(2013/08/15)

A simple and straightforward synthesis of phenyl isothiocyanates, symmetrical and unsymmetrical thioureas under ball milling
Promoted by KOH under ball milling, anilines were efficiently transformed into isothiocyanates (in presence of 5.0 equiv. CS2) or symmetrical thioureas (in presence of 1.0 equiv. CS2), without using any other harsh or toxic decomposition reagent. Some in situ generated isothiocyanates can directly "click" with other amines to afford unsymmetrical thioureas.
Zhang, Ze,Wu, Hao-Hao,Tan, Ya-Jun
p. 16940 - 16944
(2013/09/24)

Discovery of highly selective and orally active lysophosphatidic acid receptor-1 antagonists with potent activity on human lung fibroblasts
Lysophosphatidic acid is a class of bioactive phospholipid that mediates most of its biological effects through LPA receptors, of which six isoforms have been identified. The recent results from LPA1 knockout mice suggested that blocking LPA1 signaling could provide a potential novel approach for the treatment of idiopathic pulmonary fibrosis. Here, we report the design and synthesis of pyrazole- and triazole-derived carbamates as LPA1-selective and LPA1/3 dual antagonists. In particular, compound 2, the most selective LPA1 antagonist reported, inhibited proliferation and contraction of normal human lung fibroblasts (NHLF) following LPA stimulation. Oral dosing of compound 2 to mice resulted in a dose-dependent reduction of plasma histamine levels in a murine LPA challenge model. Furthermore, we applied our novel antagonists as chemistry probes and investigated the contribution of LPA1/2/3 in mediating the pro-fibrotic responses. Our results suggest LPA1 as the major receptor subtype mediating LPA-induced proliferation and contraction of NHLF.
Qian, Yimin,Hamilton, Matthew,Sidduri, Achyutharao,Gabriel, Stephen,Kondru, Rama,Narayanan, Arjun,Lucas, Matthew,Schoenfeld, Ryan C.,Laine, Dramane,Ren, Yonglin,Peng, Ruoqi,Chang, Kung-Ching,Fuentes, Maria E.,Stevenson, Christopher S.,Budd, David C.,Truitt, Terry,Hamid, Rachid,Chen, Yun,Zhang, Lin,Fretland, Adrian J.,Sanchez, Ruben Alvarez
p. 7920 - 7939,20
(2020/08/24)

Benzothiazoles: Search for anticancer agents
Novel derivatives of 2-amino benzothiazoles 4(a-j) have been synthesized and tested for their antitumor activity using National Cancer Institute (NCI) disease oriented antitumor screen protocol against nine panel of cancer cell lines. Among the synthesized compounds, two compounds were granted NSC code and screened at National Cancer Institute (NCI)-USA for anticancer activity at a single high dose (10-5 M) and five dose in full NCI 60 cell panel. Among the selected compounds, 7-chloro-N-(2,6-dichlorophenyl)benzo[d]thiazol-2- amine (4i) with GI50 values of 7.18 × 10-8 M against Non-Small Cell HOP-92 Lung Cancer cell line proved to be the most active members in this study. Virtual screening was carried out through docking the designed compounds into the ATP binding site of epidermal growth factor receptor (EGFR) to predict if these compounds have analogous binding mode to the EGFR inhibitors.
Noolvi, Malleshappa N.,Patel, Harun M.,Kaur, Manpreet
scheme or table
p. 447 - 462
(2012/10/08)

Domino synthesis of novel series of 4-substituted 5-thioxo-1,2,4- triazolidin-3-one derivatives
The efficient synthesis of 4-substituted 5-thioxo-1,2,4-triazolidin-3-one derivatives (4-substituted thiourazoles) via domino combination of thiophosgene, aliphatic or aromatic amines, and ethyl carbazate is presented.
Ghorbani-Choghamarani, Arash,Sardari, Sara
p. 1078 - 1081
(2013/08/23)

Structural optimization and structure-activity relationships of N 2-(4-(4-methylpiperazin-1-yl)phenyl)- N 8-phenyl-9 H -purine-2,8-diamine derivatives, a new class of reversible kinase inhibitors targeting both EGFR-activating and resistance mutations
This paper describe the structural optimization of a hit compound, N 2-(4-(4-methylpiperazin-1-yl)phenyl)-N8-phenyl-9H-purine- 2,8-diamine (1), which is a reversible kinase inhibitor targeting both EGFR-activating and drug-resistance (T790M) mutations but has poor binding affinity. Structure-activity relationship studies led to the identification of 9-cyclopentyl-N2-(4-(4-methylpiperazin-1-yl)phenyl)-N 8-phenyl-9H-purine-2,8-diamine (9e) that exhibits significant in vitro antitumor potency against the non-small-cell lung cancer (NSCLC) cell lines HCC827 and H1975, which harbor EGFR-activating and drug-resistance mutations, respectively. Compound 9e was further assessed for potency and selectivity in enzymatic assays and in vivo anti-NSCLC studies. The results indicated that compound 9e is a highly potent kinase inhibitor against both EGFR-activating and resistance mutations and has good kinase spectrum selectivity across the kinome. In vivo, oral administration of compound 9e at a dose of 5 mg/kg caused rapid and complete tumor regression in a HCC827 xenograft model, and an oral dose of 50 mg/kg initiated a considerable antitumor effect in an H1975 xenograft model.
Yang, Jiao,Wang, Li-Jiao,Liu, Jing-Jing,Zhong, Lei,Zheng, Ren-Lin,Xu, Yong,Ji, Pan,Zhang, Chun-Hui,Wang, Wen-Jing,Lin, Xing-Dong,Li, Lin-Li,Wei, Yu-Quan,Yang, Sheng-Yong
p. 10685 - 10699
(2013/02/22)

Environmentally benign one-pot synthesis of cyanamides from dithiocarbamates using I2 and H2O2
An environmentally benign reaction is devised for the synthesis of cyanamides from dithiocarbamate salts using iodine and H2O 2. Taylor & Francis Group, LLC.
Jamir, Latonglila,Sinha, Upasana Bora,Nath, Jayashree,Patel, Bhisma K.
experimental part
p. 951 - 958
(2012/02/01)

Isatin-β-thiosemicarbazones as potent herpes simplex virus inhibitors
A series of isatin-β-thiosemicarbazones have been designed and evaluated for antiviral activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in a plaque reduction assay. Their cytotoxicity was examined using human rhabdomyosarcoma cells (RD cells). Several derivatives of isatin-β-thiosemicarbazone exhibited significant and selective antiviral activity with low cytotoxicity. It was found that the thiourea group at thiosemicarbazone and the NH functionality at isatin were essential for their antiherpetic activity. The synthesis and structure-activity relationship studies are presented.
Kang, Iou-Jiun,Wang, Li-Wen,Hsu, Tsu-An,Yueh, Andrew,Lee, Chung-Chi,Lee, Yen-Chun,Lee, Ching-Yin,Chao, Yu-Sheng,Shih, Shin-Ru,Chern, Jyh-Haur
scheme or table
p. 1948 - 1952
(2011/05/04)

A highly efficient methodology for 5-methyl-3-aryl-2-thiooxazolidin-4-ones using lithium perchlorate in DIPEA mediated synthesis
(Chemical Equation Presented) An efficient methodology for the synthesis of 5-methyl-3-aryl-2-thiooxazolidin-4-ones from aryl isothiocyanates has been developed. Aryl isothiocyanates, synthesized from various anilines, were converted to the desired compounds by treating with ethyl lactate in presence of DIPEA and catalytic amount of lithium perchlorate. This method provides a convenient and cost-effective strategy, with no specific purification protocol.
Khatik, Gopal L.,Pal, Anang,Apsunde, Tushar D.,Nair, Vipin A.
experimental part
p. 734 - 739
(2010/08/22)