- Design, synthesis, biological evaluation and pharmacophore model analysis of novel tetrahydropyrrolo[3,4-c]pyrazol derivatives as potential TRKs inhibitors
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The tropomyosin receptor kinases TRKs are responsible for different tumor types which caused by NTRK gene fusion, and have been identified as a successful target for anticancer therapeutics. Herein, we report a potent and selectivity TRKs inhibitor 19m through rational drug design strategy from a micromolar potency hit 17a. Compound 19m significantly inhibits the proliferation of TRK-dependent cell lines (Km-12), while it has no inhibitory effect on TRK-independent cell lines (A549 and THLE-2). Furthermore, kinases selectivity profiling showed that in addition to TRKs, compound 19m only displayed relatively strong inhibitory activity on ALK. These data may indicate that compound 19m has a good drug safety. Partial ADME properties were evaluated in vitro and in vivo. Compound 19m exhibited a good AUC values and volume of distribution and low clearance in the pharmacokinetics experiment of rats. Finally, a pharmacophore model guided by experimental results is proposed. We hope this theoretical model can help researchers find type I TRK inhibitors more efficiently.
- Cheng, Maosheng,Liu, Nian,Lv, Ruicheng,Qin, Qiaohua,Sun, Yin,Sun, Yixiang,Wang, Ruifeng,Wang, Xiaoyan,Wu, Tianxiao,Yin, Wenbo,Zhang, Chu,Zhao, Dongmei
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- Palladium-Catalyzed Chlorocarbonylation of Aryl (Pseudo)Halides Through In Situ Generation of Carbon Monoxide
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An efficient palladium-catalyzed chlorocarbonylation of aryl (pseudo)halides that gives access to a wide range of carboxylic acid derivatives has been developed. The use of butyryl chloride as a combined CO and Cl source eludes the need for toxic, gaseous carbon monoxide, thus facilitating the synthesis of high-value products from readily available aryl (pseudo)halides. The combination of palladium(0), Xantphos, and an amine base is essential to promote this broadly applicable catalytic reaction. Overall, this reaction provides access to a great variety of carbonyl-containing products through in situ transformation of the generated aroyl chloride. Combined experimental and computational studies support a reaction mechanism involving in situ generation of CO.
- Bismuto, Alessandro,Boehm, Philip,Morandi, Bill,Roediger, Sven
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p. 17887 - 17896
(2020/08/19)
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- Ligand-Promoted RhIII-Catalyzed Thiolation of Benzamides with a Broad Disulfide Scope
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A ligand-promoted RhIII-catalyzed C(sp2)?H activation/thiolation of benzamides has been developed. Using bidentate mono-N-protected amino acid ligands led to the first example of RhIII-catalyzed aryl thiolation reactions directed by weakly coordinating directing amide groups. The reaction tolerates a broad range of amides and disulfide reagents.
- Kang, Yan-Shang,Zhang, Ping,Li, Min-Yan,Chen, You-Ke,Xu, Hua-Jin,Zhao, Jing,Sun, Wei-Yin,Yu, Jin-Quan,Lu, Yi
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supporting information
p. 9099 - 9103
(2019/06/13)
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- Identification of Phenylpyrazolone Dimers as a New Class of Anti-Trypanosoma cruzi Agents
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Chagas disease is becoming a worldwide problem; it is currently estimated that over six million people are infected. The two drugs in current use, benznidazole and nifurtimox, require long treatment regimens, show limited efficacy in the chronic phase of infection, and are known to cause adverse effects. Phenotypic screening of an in-house library led to the identification of 2,2′-methylenebis(5-(4-bromophenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one), a phenyldihydropyrazolone dimer, which shows an in vitro pIC50 value of 5.4 against Trypanosoma cruzi. Initial optimization was done by varying substituents of the phenyl ring, after which attempts were made to replace the phenyl ring. Finally, the linker between the dimer units was varied, ultimately leading to 2,2′-methylenebis(5-(3-bromo-4-methoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (NPD-0228) as the most potent analogue. NPD-0228 has an in vitro pIC50 value of 6.4 against intracellular amastigotes of T. cruzi and no apparent toxicity against the human MRC-5 cell line and murine cardiac cells.
- Sijm, Maarten,Siciliano de Araújo, Julianna,Ramos Llorca, Alba,Orrling, Kristina,Stiny, Lydia,Matheeussen, An,Maes, Louis,de Esch, Iwan J. P.,de Nazaré Correia Soeiro, Maria,Sterk, Geert Jan,Leurs, Rob
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supporting information
p. 1662 - 1668
(2019/08/30)
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- Acetic Acid Accelerated Visible-Light Photoredox Catalyzed N-Demethylation of N,N-Dimethylaminophenyl Derivatives
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N,N-Dimethylaminophenyl moiety is a common fragment in medicinal chemistry as several pharmaceuticals bearing this privileged motif are on the market and under clinical evaluation. Oxidative N-demethylation is generally regarded as the major metabolic pathway. However, pharmacokinetics, metabolites studies as well as the further structural modification are precluded by the impracticality of chemical synthesis. Here we report that acetic acid can significantly accelerate visible-light photoredox catalyzed N-demethylation of N,N-dimethylaminophenyl derivatives. This approach is easy for large scale reaction and even for potential industrial manufacture. (Figure presented.).
- Wu, Guolin,Li, Yazhen,Yu, Xuemei,Gao, Yu,Chen, Haijun
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supporting information
p. 687 - 692
(2017/02/23)
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- Heteroannulation enabled by a bimetallic Rh(III)/Ag(i) relay catalysis: Application in the total synthesis of aristolactam BII
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A redox-neutral bimetallic Rh(iii)/Ag(i) relay catalysis allowed the efficient construction of 3-alkylidene isoindolinones and 3-alkylidene isobenzofuranones. The Rh(iii) catalyst was responsible for the C-H monofluoroalkenylation reaction, whereas the Ag(i) salt was an activator for the follow-up cyclization. The methodology developed was applied as a key step in the rapid total synthesis of the natural product aristolactam BII.
- Ji, Wei-Wei,Lin,Li, Qingjiang,Wang, Honggen
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supporting information
p. 5665 - 5668
(2017/07/07)
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- Chelation-Assisted Nickel-Catalyzed Oxidative Annulation via Double C-H Activation/Alkyne Insertion Reaction
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A nickel/NHC system for regioselective oxidative annulation by double C-H bond activation and concomitant alkyne insertion is described. The catalytic reaction requires a bidentate directing group, such as an 8-aminoquinoline, embedded in the substrate. Various 5,6,7,8-tetrasubstituted-N-(quinolin-8-yl)-1-naphthamides can be prepared as well as phenanthrene and benzo[h]quinoline amide derivatives. Diarylalkynes, dialkylalkynes, and arylalkylalkynes can be used in the system. A Ni0/NiII catalytic cycle is proposed as the main catalytic cycle. The alkyne plays a double role as a two-component coupling partner and as a hydrogen acceptor. In two shakes: Oxidative annulation by a double C-H activation/alkyne insertion reaction was achieved by a nickel/NHC system. A Ni0/NiII catalytic cycle is proposed as the main catalytic cycle. The alkyne plays a double role as a two-component coupling partner and as a hydrogen acceptor.
- Misal Castro, Luis C.,Obata, Atsushi,Aihara, Yoshinori,Chatani, Naoto
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supporting information
p. 1362 - 1367
(2016/01/25)
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- A practical in situ generation of the schwartz reagent. reduction of tertiary amides to aldehydes and hydrozirconation
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A new, highly efficient in situ protocol (Cp2ZrCl2/LiAlH(OBu-t)3) is described for the generation of the Schwartz reagent which provides a convenient method for the amide to aldehyde reduction and the regioselective hydrozirconation-iodination of alkynes and alkenes. Highlighted are chemoselective reductions of benzamides derived by directed ortho metalation (DoM) chemistry, allowing the synthesis of valuable 1,2,3-substituted benzaldehydes. The single-step, three-component process proceeds in a very short reaction time, shows excellent functional group compatibility, and uses inexpensive and long-storage stable reducing reagents.
- Zhao, Yigang,Snieckus, Victor
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supporting information
p. 390 - 393
(2014/04/03)
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- Mild rhodium(III)-catalyzed C-H allylation with 4-vinyl-1,3-dioxolan-2-ones: Direct and stereoselective synthesis of (E)-allylic alcohols
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A rhodium(III)-catalyzed C-H direct allylation reaction with 4-vinyl-1,3-dioxolan-2-ones has been developed. The reaction provides a facile and stereoselective access to substituted-(E)-allylic alcohols under mild and redox-neutral reaction conditions. Olefinic C-H activation is applicable, giving multifunctionalized skipped dienes in good yields. Minimal double-bond migration was observed.
- Zhang, Shang-Shi,Wu, Jia-Qiang,Lao, Ye-Xing,Liu, Xu-Ge,Liu, Yao,Lv, Wen-Xin,Tan, Dong-Hang,Zeng, Yao-Fu,Wang, Honggen
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supporting information
p. 6412 - 6415
(2015/01/09)
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- Design and synthesis of 4-(4-benzoylaminophenoxy)phenol derivatives as androgen receptor antagonists
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We report the design and synthesis of novel 4-(4-benzoylaminophenoxy)phenol derivatives that bind to the androgen receptor (AR) ligand-binding domain and exhibit potent androgen-antagonistic activity. Compound 22 is one of the most potent of these derivatives, inhibiting the dihydrotestosterone-promoted growth of SC-3 cell line bearing wild-type AR (IC50 0.75 μM), LNCaP cell line bearing T877A-mutated AR (IC50 0.043 μM), and 22Rv1 cell line bearing H874Y-mutated AR (IC50 0.22 μM). Structure-activity relationship studies confirmed that the pharmacophore of these novel AR antagonists is distinct from the nitro- or cyano-substituted anilide substructure of other nonsteroidal AR antagonists. This novel pharmacophore is expected to provide a basis for designing new antiprostate cancer agents.
- Yamada, Ayumi,Fujii, Shinya,Mori, Shuichi,Kagechika, Hiroyuki
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supporting information
p. 937 - 941
(2013/10/22)
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- Palladium-catalyzed direct ortho -alkynylation of aromatic carboxylic acid derivatives
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The palladium-catalyzed direct alkynylation of C-H bonds in aromatic carboxylic acid derivatives is described. The use of 8-aminoquinoline as a directing group facilitates the alkynylation of an electronically diverse range of C(sp2)-H bonds.
- Ano, Yusuke,Tobisu, Mamoru,Chatani, Naoto
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supporting information; experimental part
p. 354 - 357
(2012/03/09)
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- Nickel-catalyzed chelation-assisted transformations involving ortho C-H bond activation: Regioselective oxidative cycloaddition of aromatic amides to alkynes
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Although the pioneering example of ortho metalation involving cleavage of C-H bonds was achieved using a nickel complex (Kleiman, J. P.; Dubeck, M. J. Am. Chem. Soc. 1963, 85, 1544), no examples of catalysis using nickel complexes have been reported. In this work, the Ni-catalyzed transformation of ortho C-H bonds utilizing chelation assistance, such as oxidative cycloaddition of aromatic amides with alkynes, has been achieved.
- Shiota, Hirotaka,Ano, Yusuke,Aihara, Yoshinori,Fukumoto, Yoshiya,Chatani, Naoto
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supporting information; experimental part
p. 14952 - 14955
(2011/11/05)
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- Synthesis and insecticidal activities of 1,3,5-trisubstituted-1,3,5- hexahydrotriazine-2-N-nitroimines
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A new series of 1,3,5-trisubstituted-1,3,5-hexahydrotriazine-2-N- nitroimines (3a-3j) were designed and synthesized as novel neonicotinoid analogues, and their structures were characterized by 1H NMR, IR, elemental analysis and MS. The preliminary bioassay tests showed that most of the target compounds had good insecticidal activities against Nilaparvata lugens as well as Aphis medicaginis at 500 mg/L, while compound 3i had 100% mortality against Nilaparvata lugens at 20 mg/L.
- Xue, Sijia,Ma, Xubo,Bu, Hongfei,Liu, Li,Xu, Xiao
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scheme or table
p. 2153 - 2156
(2012/03/26)
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- FUNGICIDE HYDROXIMOYL-TETRAZOLE DERIVATIVES
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The present invention relates to hydroximoyl-tetrazole derivatives, their process of preparation, preparation intermediate compounds, their use as fungicide active agents, particularly in the form of fungicide compositions and methods for the control of p
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Page/Page column 98
(2009/10/22)
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- Synthesis and activity of four (N,N-dimethylamino)benzamide non-steroidal anti-inflammatory drugs based on thiazole and thiazoline
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Four compounds derived from 2-aminothiazole and 2-amino-2-thiazoline were prepared by coupling the respective bases with the acid chlorides of either 3- or 4-(N,N-dimethylamino)benzoic acid. Products were identified using infrared spectroscopy. 1/su
- Lynch, Daniel E.,Hayer, Ravinder,Beddows, Samantha,Howdle, Joy,Thake, C. Douglas
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p. 191 - 197
(2007/10/03)
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- A novel series of p38 MAP kinase inhibitors for the potential treatment of rheumatoid arthritis
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The discovery, rational analogue design, synthesis and SAR of a novel bisamide class of p38 MAP kinase inhibitor are reported. The activity in vitro is described for the series. The activity in vivo and pharmacokinetic properties are exemplified for the more potent analogues, such as 18. A novel p38 MAP kinase inhibitor structural class was discovered through selectivity screening. The rational analogue design, synthesis and structure-activity relationship of this series of bis-amide inhibitors is reported. The inhibition in vitro of human p38α enzyme activity and lipopolysaccharide-induced tumour necrosis factor-α release is described for the series. The activity in vivo and pharmacokinetic properties are exemplified for the more potent analogues.
- Brown, Dearg S.,Belfield, Andrew J.,Brown, George R.,Campbell, Douglas,Foubister, Alan,Masters, David J.,Pike, Kurt G.,Snelson, Wendy L.,Wells, Stuart L.
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p. 5383 - 5387
(2007/10/03)
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- Two crystal polymorphs of 3-(dimethylamino)benzoic anhydride
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Two polymorphs of 3-(dimethylamino)benzoic anhydride have been determined by single crystal X-ray diffraction analysis. Polymorph (1) is triclinic (P1?, a 7.112(3), b 9.289(4), c 13.364(5) ?, α 96.39(2), β 104.04(2), γ 107.59(2)°, V 800.0(6) ?3
- Lynch, Daniel E.,Hayer, Ravinder,Bagga, Sanjeev,Parsons, Simon
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p. 593 - 596
(2007/10/03)
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- SYNTHESIS OF 1-ACYL- AND 1-(THIOACYL)-4-BENZYLPIPERAZINES AS POTENTIAL ANTIDEPRESSANTS
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2-Nitro, 3-nitro- and 4-nitrobenzoyl chloride were reacted with 1-benzylpiperazine in benzene in the presence of triethylamine and gave the amides IV-VI, the first of which is considered a bioisostere of the antidepressant agent piberaline (I). 2-Dimethylamino-, 3-dimethylamino- and 4-dimethylaminobenzoic acid were treated with thionyl chloride in benzene in the presence of triethylamine or pyridine, and the acid chlorides formed were reacted in situ with 1-benzylpiperazine affording the amides VII-IX.The amides I and IV - VI were transformed by treatment with phosphorus pentasulfide in pyridine to the thioamides X - XIII. 4-(Dimethylaminomethyl)benzoic acid was reacted with 1-benzylpiperazine in dimethylformamide in the presence of N,N'carbonyldiimidazole and afforded the amide XIV.Heating of ethyl 5-methylimidazole-4-carboxylate with 1-benzylpiperazine to 200 - 210 deg C gave the amide XV together with the unexpected 1-benzyl-4-ethylpiperazine (XVI).The oily or crystalline bases of the amino amides or thioamides were mostly transformed to crystalline salts and characterized by spectra.Out of the compounds prepared only X (VUFB-17070) and XIV (VUFB-17114) showed indications of efficacy in tests which are considered indicative of antidepressant activity.Compounds VII, VIII, and X appeared to be mildly antidopaminergic-similarly like piberaline (I), and compounds IV, V, XI, XIV, and XV on the contrary showed signs of dopaminominetic activity.
- Kmonicek, Vojtech,Svatek, Emil,Holubek, Jiri,Ryska, Miroslav,Valchar, Martin,Protiva, Miroslav
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p. 1817 - 1827
(2007/10/02)
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