- Kinetics and mechanism of hydrolysis of phenylureas
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The hydrolysis of phenylureas has been found to be affected by temperature, pH and buffer concentration. Kinetic evidence suggests that the formation of phenylisocyanate, the initial product in the title reaction, occurs via an intermediate zwitterion. Depending on pH and buffer concentrations, the zwitterion can be produced through three parallel routes: at low pH, specific acid-general base catalysis, followed by slow deprotonation of a nitrogen atom by a general base; at high pH, specific basic-general acid catalysis, followed by slow protonation of a N atom by a general acid; at intermediate pH the reaction proceeds through a proton switch promoted by buffers. Bifunctional acid-base buffers such as HCO3-/CO32-, H2PO42- and CH3COOH/CH3COO- are very efficient catalysts. At high buffer concentration, as well as at pH 12, the breakdown of the zwitterion is rate-determining. The results are discussed in relation to recently published papers reporting different pathways.
- Salvestrini, Stefano,Di Cerbo, Paola,Capasso, Sante
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- Synthesis and in vitro anti-bladder cancer activity evaluation of quinazolinyl-arylurea derivatives
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Based on the structural modification of molecular-targeted agent sorafenib, a series of quinazolinyl-arylurea derivatives were synthesized and evaluated for their anti-proliferative activities against six human cancer cell lines. Compared with other cell lines tested, T24 was more sensitive to most compounds. Compound 7j exhibited the best profile with lower IC50 value and favorable selectivity. In this study, we focused on 7j-induced death forms of T24 cells and tried to elucidate the reason for its potent proliferative inhibitory activity. Compound 7j treatment could trigger three different cell death forms including apoptosis, ferroptosis, and autophagy; which form would occur depended on the concentrations and incubation time of 7j: (1) Lower concentrations within the initial 8 h of 7j treatment led to apoptosis-dependent death. (2) Ferroptosis and autophagy occurred in the case of higher concentrations combining with extended incubation time through effectively regulating the Sxc?/GPx4/ROS and PI3K/Akt/mTOR/ULK1 pathways, respectively. (3) The above death forms were closely associated with intracellular ROS generation and decreased mitochondrial membrane potential induced by 7j. In molecular docking and structure-activity relationship analyses, 7j could bind well to the active site of the corresponding receptor glutathione peroxidase 4 (GPx4). Compound 7j could be a promising lead for molecular-targeted anti-bladder cancer agents’ discovery.
- Chen, Jia-Nian,Li, Ting,Cheng, Li,Qin, Tai-Sheng,Sun, Ye-Xiang,Chen, Chu-Ting,He, Yue-Zhen,Liu, Guang,Yao, Di,Wei, Ying,Li, Qiu-Yin,Zhang, Guang-Ji
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- Synthesis process of 3,4-dichlorophenyl isocyanate
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The invention discloses a synthesis process of 3,4-dichlorophenyl isocyanate. The synthesis process comprises the following steps: adding 3,4-dichloroaniline and a solvent into a reaction kettle to obtain a 3,4-dichloroaniline solution while adding solid phosgene into the reaction kettle, and heating for dissolving; when the temperature of the reaction kettle reaches 60-100 DEG C, controlling thedripping speed through a DCS to start to dropwise add the 3,4-dichloroaniline solution in the step S1, so that 3,4-dichloroaniline and solid phosgene generate 3,4-dichloroaniline hydrochloride and 3,4-dichlorobenzene methylamino acyl chloride in a solvent medium; removing hydrogen chloride from the 3,4-dichlorobenzene methylamino acyl chloride obtained in S3 to obtain 3,4-dichlorophenyl isocyanate, and after dropwise adding is finished, carrying out reflux heat preservation for 1-3 h; and removing the acid-containing solvent at normal pressure, recycling, transferring the concentrated solutionto a rectifying still, and rectifying to obtain the product 3,4-dichlorophenyl isocyanate. According to the invention, green chemicals are used as production raw materials, so that potential safety hazards caused by phosgene leakage are reduced; and common chemical solid phosgene is adopted to replace virulent phosgene to serve as an acylation reagent, and a green degradable ester solvent is adopted as a reaction medium.
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Paragraph 0026-0031
(2021/02/13)
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- Weeding composition compounded by fine glufosinate-ammonium and diuron and preparation method and application thereof
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The invention provides a weeding composition compounded by fine glufosinate-ammonium and diuron. The weeding composition is characterized by comprising fine glufosinate-ammonium, diuron and other auxiliary agents, and the content of the fine glufosinate-ammonium is 1-60 parts by mass, the content of the diuron is 1-60 parts by mass, and the content of the auxiliary agents is 20-70 parts by mass. By reasonably proportioning the proportions of the fine glufosinate-ammonium and the diuron in the herbicide, the pesticide effect of the herbicide is enhanced, the control effect on weeds in uncultivated areas is superior to the activity of the singly applied components, meanwhile, the control spectrum of the weeds is expanded, the weeding effect is improved, the weeding composition has a prominent comprehensive control effect on gramineous weeds, cyperaceae weeds and broadleaf weeds, and has the advantages of fast effectiveness, long lasting period, delayed herbicide resistance, thorough weeding, low residue, low toxicity, safety, environmental protection and the like.
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Paragraph 0033
(2021/08/07)
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- Disrupting the Conserved Salt Bridge in the Trimerization of Influenza A Nucleoprotein
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Antiviral drug resistance in influenza infections has been a major threat to public health. To develop a broad-spectrum inhibitor of influenza to combat the problem of drug resistance, we previously identified the highly conserved E339?R416 salt bridge of the nucleoprotein trimer as a target and compound 1 as an inhibitor disrupting the salt bridge with an EC50 = 2.7 μM against influenza A (A/WSN/1933). We have further modified this compound via a structure-based approach and performed antiviral activity screening to identify compounds 29 and 30 with EC50 values of 110 and 120 nM, respectively, and without measurable host cell cytotoxicity. Compared to the clinically used neuraminidase inhibitors, these two compounds showed better activity profiles against drug-resistant influenza A strains, as well as influenza B, and improved survival of influenza-infected mice.
- Woodring, Jennifer L.,Lu, Shao-Hung,Krasnova, Larissa,Wang, Shih-Chi,Chen, Jhih-Bin,Chou, Chiu-Chun,Huang, Yi-Chou,Cheng, Ting-Jen Rachel,Wu, Ying-Ta,Chen, Yu-Hou,Fang, Jim-Min,Tsai, Ming-Daw,Wong, Chi-Huey
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supporting information
p. 205 - 215
(2020/01/02)
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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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- Pentafluorosulfanyl-containing triclocarban analogs with potent antimicrobial activity
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Concerns have been raised about the long-term accumulating effects of triclocarban, a polychlorinated diarylurea widely used as an antibacterial soap additive, in the environment and in human beings. Indeed, the Food and Drug Administration has recently banned it from personal care products. Herein, we report the synthesis, antibacterial activity and cytotoxicity of novel N,N'-diarylureas as triclocarban analogs, designed by reducing one or more chlorine atoms of the former and/or replacing them by the novel pentafluorosulfanyl group, a new bioisostere of the trifluoromethyl group, with growing importance in drug discovery. Interestingly, some of these pentafluorosulfanyl-bearing ureas exhibited high potency, broad spectrum of antimicrobial activity against Gram-positive bacterial pathogens, and high selectivity index, while displaying a lower spontaneous mutation frequency than triclocarban. Some lines of evidence suggest a bactericidal mode of action for this family of compounds.
- Pujol, Eugènia,Blanco-Cabra, Núria,Julián, Esther,Leiva, Rosana,Torrents, Eduard,Vázquez, Santiago
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supporting information
(2018/11/24)
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- With anti-tumor effect of a quinazoline-urea derivative and its application (by machine translation)
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The present invention relates to a of the general formula (II) anti-tumor function of said quinazoline-urea derivative and its application. The definition of the substituent in the general formula (II) in the specification. This invention, in order to SUO draw non-Buddhist nun and Geftinat compounds as the precursor, retention of SUO draw non-Buddhist nun the pharmocology-carbamido; at the same time, such as in reserved [...] EGFR-TKIs Geftinat, synthesis, and obtain a series of quinazoline-urea derivatives, by the in vitro activity tests, some compounds exhibit excellent anti-tumor activity, such derivatives have high research and utility value. (II). (by machine translation)
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Paragraph 0139-0142; 0165
(2016/11/02)
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- N-substituted 2-isonicotinoylhydrazinecarboxamides-new antimycobacterial active molecules
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This report presents a new modification of the isoniazid (INH) structure linked with different anilines via a carbonyl group obtained by two synthetic procedures and with N-substituted 5-(pyridine-4-yl)-1,3,4-oxadiazole-2-amines prepared by their cyclisation. All synthesised derivatives were characterised by IR, NMR, MS and elemental analyses and were evaluated in vitro for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv, Mycobacterium avium 330/88, Mycobacterium kansasii 235/80 and one clinical isolated strain of M. kansasii 6509/96. 2-Isonicotinoyl-N-(4- octylphenyl)hydrazinecarboxamide displayed an in vitro efficacy comparable to that of INH for M. tuberculosis with minimum inhibitory concentrations (MICs) of 1-2 μM. Among the halogenated derivatives, the best anti-tuberculosis activity was found for 2-isonicotinoyl-N-(2,4,6-trichlorophenyl) hydrazinecarboxamide (MIC = 4 μM). In silico modelling on the enoyl-acyl carrier protein reductase InhA confirmed that longer alkyl substituents are advantageous for the interactions and affinity to InhA. Most of the hydrazinecarboxamides, especially those derived from 4-alkylanilines, exhibited significant activity against INH-resistant nontuberculous mycobacteria. gfjh+l;kfldf.
- Rychtarcikova, Zuzana,Kratky, Martin,Gazvoda, Martin,Komloova, Marketa,Polanc, Slovenko,Kocevar, Marijan,Stolarikova, Jirina,Vinsova, Jarmila
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p. 3851 - 3868
(2014/05/20)
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- Synthesis and in vitro antitumor activity of novel diaryl urea derivatives
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A series of novel diaryl ureas containing 4-[(2-amino-6-trifluromethyl) pyrimidine-4-yl]piperazine-1-yl group were synthesized and evaluated for their cytotoxic activities in a panel of human cancer cell lines. Compared with the reference drug Sorafenib, some compounds showed more potent and a broader spectrum of anti-cancer activities. Among them, compound 2p demonstrated significant inhibitory activities against MDA-MB-231, HT-29 and MCF-7 cell lines with IC50 values of 0.016, 0.63, 0.001 μmol/L, respectively.
- Zhao, Yan-Fang,Liu, Zi-Jian,Zhai, Xin,Ge, Dan-Dan,Huang, Qiang,Gong, Ping
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p. 386 - 388
(2013/07/19)
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- A simple and efficient synthesis of diaryl ureas with reduction of the intermediate isocyanate by triethylamine
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Thirty symmetrical diaryl urea derivatives were synthesised in moderate to excellent yields from arylamine and triphosgene with triethylamine as a reducing agent for the intermediate, isocyanate. It was significant that part of the products could be collected in almost quantitative yield without column chromatography. The procedure under mild reaction conditions was tolerant of a wide range of functional groups. The structures of the compounds were determined by NMR, MS and X-ray crystallographic analyses.
- Zhou, Shuguang,Yao, Ting,Yi, Jicheng,Li, Dashuai,Xiong, Jing
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p. 315 - 319
(2013/07/27)
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- Novel VEGFR-2 kinase inhibitors identified by the back-to-front approach
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We report a novel VEGFR-2 inhibitor, developed by the back-to-front approach. Docking experiments indicated that the 3-chloromethylphenylurea motif of the lead compound occupied the back pocket of VEGFR-2 kinase. An attempt was made to enhance the binding affinity of 1 by expanding the structure to access the front pocket using a triazole linker. A library of 1,4-(disubstituted)-1H-1, 2,3-triazoles were screened in silico, and one compound (VH02) was identified with an IC50 against VEGFR-2 of 0.56 μM. VH02 showed antiangiogenic effects, inhibiting tube formation in HUVEC cells (EA.hy926) at 0.3 μM, 13 times lower than its cytotoxic dose. These enzymatic and cellular activities suggest that VH02 has potential as a lead for further optimization.
- Sanphanya, Kingkan,Wattanapitayakul, Suvara K.,Phowichit, Suwadee,Fokin, Valery V.,Vajragupta, Opa
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supporting information
p. 2962 - 2967
(2013/06/27)
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- 1-Aryl-3-(1-acylpiperidin-4-yl)urea inhibitors of human and murine soluble epoxide hydrolase: Structure-activity relationships, pharmacokinetics, and reduction of inflammatory pain
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1,3-Disubstituted ureas possessing a piperidyl moiety have been synthesized to investigate their structure-activity relationships as inhibitors of the human and murine soluble epoxide hydrolase (sEH). Oral administration of 13 1-aryl-3-(1-acylpiperidin-4-yl)urea inhibitors in mice revealed substantial improvements in pharmacokinetic parameters over previously reported 1-adamantylurea based inhibitors. For example, 1-(1-(cyclopropanecarbonyl) piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (52) showed a 7-fold increase in potency, a 65-fold increase in Cmax, and a 3300-fold increase in AUC over its adamantane analogue 1-(1-adamantyl)-3-(1-propionylpiperidin-4-yl) urea (2). This novel sEH inhibitor showed a 1000-fold increase in potency when compared to morphine by reducing hyperalgesia as measured by mechanical withdrawal threshold using the in vivo carrageenan induced inflammatory pain model.
- Rose, Tristan E.,Morisseau, Christophe,Liu, Jun-Yan,Inceoglu, Bora,Jones, Paul D.,Sanborn, James R.,Hammock, Bruce D.
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supporting information; experimental part
p. 7067 - 7075
(2010/12/25)
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- Structural optimization of a CXCR2-directed antagonist that indirectly inhibits γ-secretase and reduces Aβ
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Amyloid β (Aβ), a key molecule in the pathogenesis of Alzheimer's disease (AD), is derived from the amyloid precursor protein (APP) by sequential proteolysis via β- and γ-secretases. Because of their role in generation of Aβ, these enzymes have emerged as important therapeutic targets for AD. In the case of γ-secretase, progress has been made towards designing potent inhibitors with suitable pharmacological profiles. Direct γ-secretase inhibitors are being evaluated in clinical trials and new strategies are being explored to block γ-secretase activity indirectly as well. In this regard, we have previously reported an indirect regulation of γ-secretase through antagonism of CXCR2, a G-protein coupled receptor (GPCR). We demonstrated that N-(2-hydroxy-4-nitrophenyl)-N′-(2-bromophenyl)urea (SB225002), a selective inhibitor of CXCR2 also plays a role in an indirect inhibition of γ-secretase. Furthermore, we reported a ～5-fold difference in the selective inhibition of APP versus Notch processing via γ-secretase following treatment with SB225002. Herein we describe the synthesis and optimization of SB225002. By determination of the structure-activity relationship (SAR), we derived small molecules that inhibit Aβ40 production with IC50 values in the sub-micromolar range in a cell-based assay and also validated the potential of CXCR2 as a new target for therapeutic intervention in AD.
- Bakshi, Pancham,Jin, Chao,Broutin, Pierre,Berhane, Beniam,Reed, Jon,Mullan, Michael
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experimental part
p. 8102 - 8112
(2010/03/24)
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- A facile method for preparation of aromatic isocyanates using bis(trichloromethyl)carbonate
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A facile synthesis of aromatic isocyanates using bis(trichloromethyl)carbonate (BTC) is reported with high yields of products. BTC is used to supply phosgene in situ in stoichiometric amounts.
- Xu, Zhenyuan,Du, Xiaohue,Su, Weike
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p. 962 - 963
(2007/10/03)
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- Synthesis of new substituted 6-ureidopurines and 6-ureido-9-(2,3,5-triacetyl ribofuranosyl)purines having cytokinin (plant growth promoting) activity
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Substituted 6-ureidopurines 6a-j and 6-ureido-9-(2,3,5-triacetylribofuranosyl) purines 7a-j have been synthesized by condensing substituted phenyl isocyanates with adenine 3 and 2,3,5-triacetyladenosine 5 respectively in pyridine. Substituted phenyl isocyanates 2a-j are prepared from substituted anilines 1a-j in the presence of triphosgene and triethylamine in dry benzene. Compounds 6a-j and 7a-j have been evaluated for cytokinin activity on seeds of Raphanus sativus, family Brassicaceae (common name white radish) at 5 different concentrations in distilled water ranging from 0.001 to 10 mg litre-1. Compounds 6a, 7a, 7b and 7i having substitutents at 3 position of phenyl ring are found to show higher cytokinin activity than benzyladenine at all concentrations (Table II).
- Mhatre, Vandana,Joshi, Vidya
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p. 2667 - 2675
(2007/10/03)
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- Synthesis, selective aldose reductase inhibitory profile and antihyperglycaemic potential of certain parabanic acid derivatives
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Synthesis and aldose reductase inhibitory profile of certain parabanic acid derivatives 1a-p is described. Also, the antihyperglycaemic potential of these compounds was studied. The most active inhibitors in this series were compounds 1 g, 1p, and 1o which showed inhibitory activity, 36.6, 90 and 91% respectively, at concentration 1 × 10-4. Their IC50 were 2 × 10-6, 7.5 × 10-8 and 5 × 10-8, respectively. Compound 1o exhibited pronounced antihyperglycaemic effect.
- Nabil Aboul-Enein,El-Azzounya,Maklad,Attia,Wiese
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p. 329 - 350
(2007/10/03)
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- Synthesis of isocyanates from carbamate esters employing boron trichloride
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The conversion of carbamate esters to isocyanates and diisocyanates of industrial importance is possible using BCl3 in the presence of Et3N; the reaction is simple in execution and work-up, occurring under mild conditions and affording isocyanates in excellent yields.
- Butler,Alper
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p. 2575 - 2576
(2007/10/03)
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- THE KINETIC RELATIONSHIPS OF THE REACTIONS OF N-ARYL-3-METHYLPYRAZOLE-1-CARBOXAMIDES WITH AMINES
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The kinetics of the reaction of N-aryl-3-methylpyrazole-1-carboxamides with amines in carbon tetrachloride are described by an equation of third order in the substituted amide.At small concentrations the amine does not take part in the controlling stage of the reaction, but the transamination rate increases with increase in the concentration of the amine.It was concluded on the basis of the obtained results that the rate-controlling stages are the thermal dissociation of the substituted amide and of its complexes with amino compounds.
- Ivanov, M. G.,Elizarova, T. P.,Dergunov, Yu. I.
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p. 450 - 455
(2007/10/02)
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- THE EFFECT OF SOLVENTS ON THE KINETICS OF TRANSAMINATION OF N-ARYL-3-METHYLPYRAZOLE-1-CARBOXAMIDES
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The effect of substituents in the aromatic ring on the kinetics of the reaction of N-aryl-3-methylpyrazole-1-carboxamides with amines in various aprotic solvents is described by the Hammett equation with small positive values of ρ.A reaction mechanism, according to which the controlling stage is the removal of a proton from the nitrogen atom of the amide group, is proposed on the basis of these results and also of study of the effect of additions of hydroxyl-containing compounds.
- Ivanov, M. G.,Elizarova, T. P.,Dergunov, Yu. I.
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p. 456 - 460
(2007/10/02)
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- Herbicidally active methyl-substituted tetrahydro-2-pyrimidinone derivatives
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Methyl-substituted tetrahydro-2-pyrimidinone derivatives of the general formula STR1 in which each Ar, independently of each other, represents an aryl group which is optionally mono- or poly-substituted by substituent(s) selected from halogen, C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkylthio, nitro, phenoxy and trifluoromethyl, and R1, R2 and R3 independently represent a hydrogen atom or a methyl group, provided that at least one of R1, R2 and R3 represents a methyl group, are new and find use as herbicides, in particular as selective herbicides which may be used on weeds in crops such as cotton and rice. The N,N'-diaryl-N-haloalkyl-ureas which are starting materials for the production of compounds of formula (I) are also new.
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- THERMAL DECOMPOSITION OF SUBSTITUTED UREAS
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The thermal dissociation of N,N'-diaryl- and N,N-dimethyl-N'-aryl-ureas was investigated under isothermal conditions in absence of solvent.In the case of N,N-dimethyl-N'-arylureas enthalpies of reaction were determined, and their relation to Hammett ? constants was shown.
- Chimishkyan, A. L.,Svetlova, L. P.,Leonova, T. V.,Gluyaev, N. D.
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p. 1317 - 1320
(2007/10/02)
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