- Ligand-based optimization to identify novel 2-aminobenzo[d]thiazole derivatives as potent sEH inhibitors with anti-inflammatory effects
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Inhibition of the soluble epoxide hydrolase (sEH) is a promising new therapeutic approach in the treatment of inflammation. Driven by the in-house database product lead 1, a hybridization strategy was utilized for the design of a series of novel benzo [d]thiazol derivatives. To our delight, D016, a byproduct of compound 9, was obtained with an extraordinarily low IC50 value of 0.1 nM but poor physical and chemical properties. After removal of a non-essential urea moiety or replacement of the urea group by an amide group, compounds 15a, 17p, and 18d were identified as promising sEH inhibitors, and their molecular binding modes to sEH were constructed. Furthermore, compounds 15a and 18d exhibited more effective in vivo anti-inflammatory effect than t-AUCB in carrageenan-induced mouse paw edema. Compound 15a also showed moderate metabolic stability with a half-time of 34.7 min. Although 18d was unstable in rat liver microsomes, it might be a “prodrug”. In conclusion, this study could provide valuable insights into discovery of new sEH inhibitors, and compounds 15a and 18d were worthy of further development as potential drug candidates to treat inflammation.
- Han, Yufei,Huang, Desheng,Xu, Sicong,Li, Lingling,Tian, Ye,Li, Shuo,Chen, Cong,Li, Yingxiu,Sun, Yanping,Hou, Yunlei,Sun, Yongjun,Qin, Mingze,Gong, Ping,Gao, Zibin,Zhao, Yanfang
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- Design, synthesis, and biological evaluation of sorafenib derivatives containing indole (ketone) semicarbazide analogs as antitumor agents
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A series of new sorafenib derivatives was designed and synthesized. The antiproliferative activity of the synthesized compounds against human lung cancer cell (A549), human pancreatic cancer cell (PC-3), human leukemia cell (K562), and human hepatoma cell (SMMC-7721) was evaluated by MTT assay. The results revealed that several compounds displayed more significant antitumor activities than commercial anticancer agent sorafenib against SMMC-7721. In addition, compounds 7a, 7g, 7l, 7m, and 7p represented obvious growth inhibition with IC50 values of 1-9 μM against four cancer cell lines, demonstrating more predominant activities against cancer cells as compared to sorafenib. Furthermore, some structure-activity relationships have also been established. Compounds containing indole and benzene ring substituted by halogen showed better activity than sorafenib. Wound healing assay suggested that cells would be targeted on their migratory capacity by 7g, potentially affecting the migration activity of these tumors. The effects of A549 and PC-3 cell apoptosis induced by compound 7g were significantly increased compared with sorafenib. Importantly, the result of western blot assay showed that 7g inhibited cell growth by suppressing the activity of EGFR, especially the expression of p-EGFR (Tyr1068).
- Li, Wen,Qi, Ya-Yun,Wang, Yuan-Yuan,Gan, Yi-Yuan,Shao, Li-Hui,Zhang, Li-Qiong,Tang, Zhen-Hua,Zhu, Mei,Tang, Si-Yu,Wang, Zhen-Chao,Ouyang, Gui-Ping
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p. 2548 - 2560
(2020/04/02)
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- Discovery of 4-piperazinyl-2-aminopyrimidine derivatives as dual inhibitors of JAK2 and FLT3
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Hybridization strategy is an effective strategy to obtain multi-target inhibitors in drug design. In this study, we assembled the pharmacophores of momelotinib and tandutinib to get a series of 4-piperazinyl-2-aminopyrimidine derivatives. All compounds were tested for the inhibition of JAK2 and FLT3 enzymes, of which, compounds with potent enzyme activities were assayed for antiproliferative activities against three cancer cell lines (HEL, MV4-11, and HL60). The structure-activity relationship studies were conducted through variations in two regions, the “A” phenyl ring and “B” phenyl ring. Compound 14j showed the most balanced in vitro inhibitory activity against JAK2 and FLT3 (JAK2 IC50 = 27 nM, FLT3 IC50 = 30 nM), and it also showed potent inhibition against the above tested cell lines. In the cellular context, 14j strongly induced apoptosis by arresting cell cycle in the G1/S phase, and was selected as a promising JAK2/FLT3 dual inhibitor.
- Li, Yingxiu,Ye, Tianyu,Xu, Le,Dong, Yuhong,Luo, Yong,Wang, Chu,Han, Yufei,Chen, Ke,Qin, Mingze,Liu, Yajing,Zhao, Yanfang
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- Tyrosine kinase inhibitor and application thereof
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The invention discloses a tyrosine kinase inhibitor. A chemical name of the tyrosine kinase inhibitor is 1-(2-chloro-4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)-3-(4-fluorophenyl)carbamide and a structure is shown as a formula (I). Meanwhile, the inventio
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Paragraph 0015; 0036; 0040; 0041
(2018/09/08)
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- Tyrosine kinase inhibitor and application thereof
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The invention discloses a tyrosine kinase inhibitor. A chemical name of the tyrosine kinase inhibitor is 1-(2-chloro-4-((6,7-dimethoxyquinoline-4-yl)oxy)phenyl)-3-(4-fluorophenyl)carbamide and a structure is shown as a formula (I). Meanwhile, the inventio
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Paragraph 0040; 0041
(2018/09/08)
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- Arylureas derived from colchicine: Enhancement of colchicine oncogene downregulation activity
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Our efforts to get therapeutically useful colchicine derivatives for the treatment of cancer have led us to synthetize and biologically evaluate twenty-seven N,N′-disubstituted ureas containing a colchicine moiety and an aryl fragment. The cytotoxicity of
- Blasco, Víctor,Cu?at, Ana C.,Sanz-Cervera, Juan F.,Marco, J. Alberto,Falomir, Eva,Murga, Juan,Carda, Miguel
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p. 817 - 828
(2018/04/02)
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- Highly Regioselective Carbamoylation of Electron-Deficient Nitrogen Heteroarenes with Hydrazinecarboxamides
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The use of hydrazinecarboxamides as a new class of carbamoylating agents has been established through the dehydrazinative Minisci reaction of electron-deficient nitrogen heteroarenes. A wide range of electron-deficient nitrogen heteroarenes, including isoquinoline, quinoline, pyridine, phenanthridine, quinoxaline, and phthalazine, underwent copper/acid-catalyzed oxidative carbamoylation with hydrazinecarboxamide hydrochlorides to afford structurally diverse nitrogen-heteroaryl carboxamides as single regioisomers in moderate to excellent yields. The functional group tolerance was substantially demonstrated in the direct carbamoylation of quinine obviating multistep sequences involving protecting groups and prefunctionalization of the heterocycle.
- He, Zeng-Yang,Huang, Chao-Fan,Tian, Shi-Kai
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supporting information
p. 4850 - 4853
(2017/09/23)
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- Synthesis of N-aryl and N-arylcarbamoylamino derivatives of 1,3-diazinane-5-carboxamide and their activity against glioblastoma LN-229 cell line
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Six structural motifs based on the initial (lead) structure of merbarone were designed, prepared, and tested against the glioblastoma LN-229 cell line. Three different structural moieties were modified in the search for optimal glioblastoma activity: the 1,3-diazinane moiety, the aryl moiety, and the heteroatom linker. Calculated molecular descriptors such as lipophilicity (C log P), acidic strength (calculated pKa), and polar surface area (PSA) were used to design a diverse structural library of these compounds. From six different structural motifs and 136 compounds, a handful of examples with moderate (100 μg/ml), good (10 μg/ml) and excellent (1 μg/ml) glioblastoma activity were elucidated.
- Hron, Rebecca J.,Jursic, Branko S.,Neumann, Donna M.
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p. 6183 - 6193
(2016/12/06)
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- TRPV1 modulators: Synthesis and in vitro evaluation of 1-heteroaryl piperidinecarboxamide and piperazinylurea derivatives
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Abstract A series of new 1-heteroaryl piperidinecarboxamide and piperazinylurea derivatives was synthesized and evaluated as TRPV1 modulators in a Ca2+ channel assay in HEK-293 cells overexpressing the human recombinant TRPV1 channel. Structura
- Congiu, Cenzo,Onnis, Valentina,Balboni, Gianfranco,Schiano-Moriello, Aniello,Di Marzo, Vincenzo,De Petrocellis, Luciano
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p. 129 - 138
(2015/06/22)
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- CARBAMATE COMPOUNDS AND METHODS OF USE IN DISEASES OF THE NERVOUS SYSTEM
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In general, among other things, compounds of Formula I are provided: or a pharmaceutically acceptable salt thereof, in which R1-7 9-10 are each independently selected from the group consisting of hydrogen, hydroxy, alkoxy, and alkyl; and R8 is selected from the group consisting of fluoro, iodo, and tributyltin. Other compounds are also provided. Methods of treatment and diagnosis are also provided.
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Paragraph 00105; 00115
(2014/03/26)
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- 3-(7-Dimethylamino)coumarin N-phenylsemicarbazones in solution and polymer matrices: Tuning their fluorescence via para-phenyl substitution
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The photo-physical properties of five new para-phenyl substituted derivatives of 3-(7-dimethylamino)coumarin N-phenylsemicarbazone with various electron-withdrawing substituents R (RF, Br, CF3, CN or NO 2) in the para-position on the phenyl ring were investigated in solvents and in polymer matrices. Tuning their fluorescent properties via para-substitution is discussed in terms of Twisted Intra-molecular Charge-Transfer (TICT) state formation, specific solute-solvent interactions (hydrogen bonding), fluorescent H-aggregates formation, and the solvent polarity and polymer matrix effects.
- Cigáň, Marek,Danko, Martin,Donovalová, Jana,Ga?par, Jan,Stankovi?ová, Henrieta,Gáplovsky, Anton,Hrdlovi?, Pavol
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- 4,5-DIHYDROISOXAZOLE DERIVATIVES AS NAMPT INHIBITORS
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The present invention provides substituted 4,5-dihydroisoxazole derivatives of formula (I), which may be therapeutically useful, more particularly NAMPT inhibitors and in which R1 R2, Y, X, "Het" and "p" have the meanings given in the specification, and pharmaceutically acceptable salts thereof that are useful in the treatment and prevention of diseases or disorder caused by an elevated level of nicotinamide phosphoribosyltransferase (NAMPT) in a mammal. The present invention also provides preparation of the compounds and pharmaceutical formulations comprising at least one of the substituted 4,5-dihydroisoxazole derivatives of formula (I) or a pharmaceutically acceptable salts or stereoisomers or N-oxide thereof.
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Page/Page column 40; 41
(2014/08/06)
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- Synthesis and evaluation in vitro of 1-[2-(10-dihydroartemisininoxy) ethyl]-3-phenylurea derivatives as potential agents against cancer
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In order to develop potent and selective anticancer agents, a series of novel artemisinin derivatives bearing urea moiety 1a-n were facilely synthesized herein and screened for their activities in vitro against ten human tumor cell lines (HeLa, MCF-7, U937, K562, HL60, HCT116, HepG2, A549, A375-S2, and HT1080). The pharmacological results indicated that some compounds showed excellent activity against cancer cell lines and good selectivity, especially the compound 1c which proved to be the most active against the cancer cells as well as distinctive patterns of selectivity.
- Luo, Wei,Xia, Ming-Yu,Ikejima, Takashi,Li, Li-Hua,Guo, Chun
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p. 3170 - 3176
(2013/07/19)
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- Synthesis and biological evaluation of 4-phenoxy-6,7-disubstituted quinolines possessing semicarbazone scaffolds as selective c-Met inhibitors
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Novel quinoline derivatives bearing acyclic semicarbazones were prepared and their chemical structures as well as the relative stereochemistry were confirmed. All the synthesized compounds were evaluated for their c-Met kinase inhibitory activity and their cytotoxicity against the cell lines HT-29, MKN-45, and MDA-MB-231 in vitro. Several potent compounds were further evaluated against A549 cells. Most compounds displayed moderate to excellent activity, and the structure-activity relationship studies identified the most promising compound 35 as a selective c-Met kinase inhibitor (IC50 = 4.3 nM). Compound 35 showed a 3.5- and 18.8-fold increase in cytotoxicity in vitro against HT-29 and A549 cells, respectively, compared to that of foretinib. Poor off-target effects of compound 35 were further confirmed by the antiproliferative activity against the c-Met inhibition less sensitive MDA-MB-231 cell line (IC50 = 0.77 μM). Copyright
- Qi, Baohui,Tao, Haiyan,Wu, Di,Bai, Jinying,Shi, Yandan,Gong, Ping
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p. 596 - 609
(2013/09/02)
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- Unprecedented "in water" imidazole carbonylation: Paradigm shift for preparation of urea and carbamate
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The first "In Water" imidazolecarbonylation of amine is described. A one pot reaction of carbonylimidazolide in water with a nucleophile provides an efficient and general method for the preparation of urea, carbamates and thiocarbamates. Use of an anhydrous solvent and an inert atmosphere could be avoided. Product precipitate out from the reaction mixture and can be obtained in high purity by filtration, resulting in a simple and scalable method.
- Padiya, Kamlesh J.,Gavade, Sandip,Kardile, Bhavana,Tiwari, Manojkumar,Bajare, Swapnil,Mane, Madhav,Gaware, Vivek,Varghese, Shaji,Harel, Dipak,Kurhade, Suresh
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p. 2814 - 2817
(2012/08/07)
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- Synthesis and antimalarial activity of novel dihydro-artemisinin derivatives
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The Plasmodium falciparum cysteine protease falcipain-2, one of the most promising targets for antimalarial drug design, plays a key role in parasite survival as a major peptide hydrolase within the hemoglobin degradation pathway. In this work, a series of novel dihydroartemisinin derivatives based on (thio)semicarbazone scaffold were designed and synthesized as potential falcipain-2 inhibitors. The in vitro biological assay indicated that most of the target compounds showed excellent inhibition activity against P. falciparum falcipain-2, with IC50 values in the 0.29-10.63 μM range. Molecular docking studies were performed to investigate the binding affinities and interaction modes for the inhibitors. The preliminary SARs were summarized and could serve as a foundation for further investigation in the development of antimalarial drugs.
- Liu, Yang,Cui, Kunqiang,Lu, Weiqiang,Luo, Wei,Wang, Jian,Huang, Jin,Guo, Chun
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experimental part
p. 4527 - 4538
(2011/08/10)
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- Design and synthesis of novel triazole antifungal derivatives by structure-based bioisosterism
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The incidence of life-threatening fungal infections is increasing dramatically. In an attempt to develop novel antifungal agents, our previously synthesized phenoxyalkylpiperazine triazole derivatives were used as lead structures for further optimization. By means of structure-based bioisosterism, triazolone was used as a new bioisostere of oxygen atom. This type of bioisosteric replacement can improve the water solubility without loss of hydrogen-bonding interaction with the target enzyme. A series of triazolone-containing triazoles were rationally designed and synthesized. As compared with fluconazole, several compounds showed higher antifungal activity with broader spectrum, suggesting their potential for further evaluations.
- Sheng, Chunquan,Che, Xiaoying,Wang, Wenya,Wang, Shengzheng,Cao, Yongbing,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian
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experimental part
p. 5276 - 5282
(2011/12/03)
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- Synthesis and characterization of vanillin semicarbazones
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Semicarbazones have a great interest because of their chemistry and biological activities for the treatment of various human ailments. A series of seven vanillin semicarbazones (3a-g) were synthesized by reflux of aryl semicarbazides with appropriate carbonyl compound in the presence of glacial acetic acid. The aryl semicarbazides (2a-g) were synthesized from aryl carbamates by reacting with hydrazine hydrate and ethanol on hydrazinolysis. The aryl carbamates (1a-g) were obtained by the reaction between phenyl chloro formate and aniline/substituted aniline in anhydrous ether in the presence of sodium hydroxide. The structure of the newly synthesized compounds was established by various analytical techniques such as IR, 1H NMR and MASS spectral studies.
- Venkateshhan,Ravichandiran,Selvakumar,Lavakumar
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experimental part
p. 4632 - 4634
(2012/02/04)
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- TRIAZOLONE DERIVATIVES AS ANTI-INFLAMMATORY AGENTS
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The present invention relates to novel triazolone derivatives as anti-inflammatory agents. The compounds described herein can be useful for inhibition and prevention of inflammation and associated pathologies including inflammatory and autoimmune diseases
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Page/Page column 19
(2010/11/24)
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- Preparation of N-substituted aryl and alkyl carbamates and their inhibitory effect on oat seed germination.
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A series of N-substituted aryl and alkyl carbamates (RNHCOOR'; R: aryl, alkyl; R': aryl, alkyl) was prepared and screened for inhibitory activity toward the germination of oat seeds. The activity of each compound was compared with that of chlorpropham (isopropyl 3-chlorocarbanilate). Some of the synthetic carbamates possessing the N-(phenylthio)methyl group, PhSCH2NHCOOR', showed inhibitory activity close or comparable to that of chlorpropham.
- Alizadeh, Babak Heidary,Sugiyama, Takeyoshi,Oritani, Takayuki,Kuwahara, Shigefumi
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p. 422 - 425
(2007/10/03)
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- Optically active antifungal azoles. VI. Synthesis and antifungal activity of N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl) propyl]-N′-(4-substituted phenyl)-3(2H,4H)-1,2,4-triazolones and 5(1H,4H)-tetrazolones
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A new series of optically active antifungal azoles, N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl) propyl]-N′-(4-substituted phenyl)-3(2H,4H)-1,2,4-triazolones (1,2) and 5(1H,4H)-tetrazolones (3), were prepared from the triflate derivative of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (13) by an SN2 displacement reaction with the union of an azolone (17-19) and subsequent ring-opening reaction with 1H-1,2,4-triazole. The optically active oxiranylethanol 13 was synthesized from methyl (R)-lactate in a stereocontrolled manner. The azolones 1-3 prepared showed potent antifungal activities in vitro and in vivo.
- Kitazaki, Tomoyuki,Tamura, Norikazu,Tasaka, Akihiro,Matsushita, Yoshihiro,Hayashi, Ryogo,Okonogi, Kenji,Itoh, Katsumi
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p. 314 - 327
(2007/10/03)
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