- Design, synthesis, and biological activity evaluation of 2-(benzo[b]thiophen-2-yl)-4-phenyl-4,5-dihydrooxazole derivatives as broad-spectrum antifungal agents
-
To discover antifungal compounds with broad-spectrum and stable metabolism, a series of 2-(benzo[b]thiophen-2-yl)-4-phenyl-4,5-dihydrooxazole derivatives was designed and synthesized. Compounds A30-A34 exhibited excellent broad-spectrum antifungal activity against Candida albicans with MIC values in the range of 0.03–0.5 μg/mL, and against Cryptococcus neoformans and Aspergillus fumigatus with MIC values in the range of 0.25–2 μg/mL. In addition, compounds A31 and A33 showed high metabolic stability in human liver microsomes in vitro, with the half-life of 80.5 min and 69.4 min, respectively. Moreover, compounds A31 and A33 showed weak or almost no inhibitory effect on the CYP3A4 and CYP2D6. The pharmacokinetic evaluation in SD rats showed that compound A31 had suitable pharmacokinetic properties and was worthy of further study.
- Zhao, Liyu,Sun, Yin,Yin, Wenbo,Tian, Linfeng,Sun, Nannan,Zheng, Yang,Zhang, Chu,Zhao, Shizhen,Su, Xin,Zhao, Dongmei,Cheng, Maosheng
-
-
- Design, synthesis, and biological evaluation of benzo[b]thiophene 1,1-dioxide derivatives as potent STAT3 inhibitors
-
As a member of the signal transducer and activator of transcription (STAT) family, STAT3 plays a critical role in several biological pathways such as cell proliferation, migration, survival, and differentiation. Due to abnormal continuous activation in tumors, inhibition of STAT3 has emerged as an attractive approach for the treatment of various cancer cells. Herein, we report a series of novel STAT3 inhibitors based on benzo[b]thiophene 1,1-dioxide scaffold and evaluated their anticancer potency. Among them, compound 8b exhibited the best activity against cancer cells. Compound 8b induced apoptosis and blocked the cell cycle. Meanwhile, 8b reduced intracellular ROS content and caused the loss of mitochondrial membrane potential. Further research revealed that 8b significantly blocked STAT3 phosphorylation and STAT3-dependent dual-luciferase reporter gene experiments showed that compound 8b has a marked inhibition of STAT3-mediated Firefly luciferase activity. Molecular modeling studies revealed compound 8b occupied the pocket well with the SH2 domain in a favorable conformation.
- Li, Wen-Zhen,Xi, Hui-Zhi,Wang, Yi-Jie,Ma, Hong-Bo,Cheng, Zhi-Qiang,Yang, Yu,Wu, Meng-Ling,Liu, Ting-Mei,Yang, Wen,Wang, Qin,Liao, Meng-Ya,Xia, Yong,Zhang, Yi-Wen
-
p. 835 - 849
(2021/09/02)
-
- Ag(I)-Catalyzed C-H Carboxylation of Thiophene Derivatives
-
CO2utilization is an attractive aspect as it allows the direct conversion of CO2into valuable chemicals. In this regard, direct incorporation of CO2into the C-H bond of heteroaromatic compounds is important due to the ubiquitous structural motifs of the heteroaromatic carboxylic acids. Herein, we report the Ag-catalyzed C-H carboxylation of thiophene derivatives. This new catalytic system involving a phosphine ligand and lithiumtert-butoxide enables the direct carboxylation of thiophenes under mild reaction conditions. Experimental studies revealed that the use oftert-butyl alkoxide is critical for the exergonic formation of an arylsilver intermediate, and the results were further supported by density functional theory calculations.
- Lee, Mijung,Hwang, Young Kyu,Kwak, Jaesung
-
p. 3136 - 3144
(2021/09/30)
-
- HDAC inhibitor and preparation method and application thereof
-
The present invention discloses a compound represented by a formula I, a stereoisomer thereof, and a pharmaceutically acceptable salt thereof. The invention further relates to a pharmaceutical composition containing the compound shown in the formula I and application of the compound in preparation of HDAC inhibitor drugs. The compound or the pharmaceutical composition thereof can be used for treating cell proliferation diseases, autoimmune diseases, inflammation, neurodegenerative diseases or viral diseases.
- -
-
Paragraph 0219-0222
(2020/11/12)
-
- Discovery of fluorescent coumarin-benzo[b]thiophene 1, 1-dioxide conjugates as mitochondria-targeting antitumor STAT3 inhibitors
-
STAT3 has been extensively studied as a potential antitumor target. Though studies on regulating STAT3 mainly focus on the inhibition of STAT3 phosphorylation at Tyr705 residue, the phosphorylation at Ser727 residue of STAT3 protein is also closely associated with the mitochondrial import of STAT3 protein. N, N-diethyl-7-aminocoumarin is a fluorescent mitochondria-targeting probe. In this study, a series of STAT3 inhibitors were developed by connecting N, N-diethyl-7-aminocoumarin fluorophore with benzo [b]thiophene 1, 1-dioxide moiety. All designed compounds displayed potent anti-proliferative activity against cancer cells. The representative compound 7a was mainly accumulated in mitochondria visualized by its fluorescence. STAT3 phosphorylation was inhibited by compound 7a at both Tyr705 and Ser727 residues. Compound 7a inhibited STAT3 phosphorylation whereas had no influence on the phosphorylation levels of STAT1, JAK2, Src and Erk1/2, indicating good selectivity of compound 7a. Moreover, compound 7a down-regulated the expression of STAT3 target genes Bcl-2 and Cyclin D1, increased ROS production and remarkably reduced the mitochondrial membrane potential to induce mitochondrial apoptotic pathway. Furthermore, compound 7a in vivo suppressed breast cancer 4T1 implanted tumor growth. Taken together, these results highlighted that compound 7a might be a promising mitochondria-targeting STAT3 inhibitor for cancer therapy.
- Cai, Guiping,Yu, Wenying,Song, Dongmei,Zhang, Wenda,Guo, Jianpeng,Zhu, Jiawen,Ren, Yuhao,Kong, Lingyi
-
p. 236 - 251
(2019/05/02)
-
- Histone deacetylase inhibitor as well as preparation method and application thereof
-
The invention discloses a histone deacetylase inhibitor. The invention furthermore discloses a compound shown as a formula I and stereisomers thereof. The novel compound shown as the formula I disclosed by the invention shows excellent histone deacetylase inhibitory activity, and provides a novel medical probability for clinical treatment of histone deacetylase activity abnormality-related diseases.
- -
-
Paragraph 0099-0103
(2019/10/01)
-
- RHO-ASSOCIATED PROTEIN KINASE INHIBITOR, PHARMACEUTICAL COMPOSITION COMPRISING THE SAME, AS WELL AS PREPARATION METHOD AND USE THEREOF
-
The present invention relates to a Rho-associated protein kinase inhibitor of Formula (I), a pharmaceutical composition comprising the same, a preparation method thereof, and use thereof for the prevention or treatment of a disease mediated by the Rho-associated protein kinase (ROCK).
- -
-
Paragraph 0148; 0149
(2019/01/11)
-
- RHO-ASSOCIATED PROTEIN KINASE INHIBITOR, PHARMACEUTICAL COMPOSITION COMPRISING THE SAME, AS WELL AS PREPARATION METHOD AND USE THEREOF
-
The present invention relates to a Rho-associated protein kinase inhibitor of Formula (I), a pharmaceutical composition comprising the same, a preparation method thereof, and use thereof for the prevention or treatment of a disease mediated by the Rho-associated protein kinase (ROCK).
- -
-
Paragraph 0146; 0147
(2019/01/11)
-
- Antagonizing STAT3 activation with benzo[b]thiophene 1, 1-dioxide based small molecules
-
STAT3 is an attractive therapeutic target for cancer therapy. However, due to low potency or poor druggability, none of its inhibitors are clinically available. Herein, a series of aminobenzo[b]thiophene 1, 1-dioxides with good drug-likeness properties were designed, synthesized and evaluated as STAT3 inhibitors. Most of them exhibited higher antitumor activity than the small-molecule STAT3 inhibitor, Stattic. Compound 15 was the most potent and had an IC50range in 0.33–0.75?μM in various cancer cell lines. The overexpressed and IL-6 induced phosphorylation levels of STAT3 were both inhibited by 15 without influencing the phosphorylation levels of the upstream kinases Src and Jak2. 15 also suppressed the expressions of STAT3 downstream gene, Bcl-2. 15 effectively increased the ROS levels of cancer cells, induced cancer cell apoptosis and abolished the colony formation ability of cancer cells without affecting bypass kinase p-Erk. Furthermore, 15 in?vivo induced significant antitumor responses, and exhibited less toxicity than Doxorubicin. Together, this study described a class of new STAT3 inhibitors as antitumor agents.
- Zhang, Wenda,Ma, Ting,Li, Shanshan,Yang, Yanwei,Guo, Jianpeng,Yu, Wenying,Kong, Lingyi
-
p. 538 - 550
(2016/10/11)
-
- Reinvestigating Old Pharmacophores: Are 4-Aminoquinolines and Tetraoxanes Potential Two-Stage Antimalarials?
-
The syntheses and antiplasmodial activities of various substituted aminoquinolines coupled to an adamantane carrier are described. The compounds exhibited pronounced in vitro and in vivo activity against Plasmodium berghei in the Thompson test. Tethering a fluorine atom to the aminoquinoline C(3) position afforded fluoroaminoquinolines that act as intrahepatocytic parasite inhibitors, with compound 25 having an IC50 = 0.31 μM and reducing the liver load in mice by up to 92% at 80 mg/kg dose. Screening our peroxides as inhibitors of liver stage infection revealed that the tetraoxane pharmacophore itself is also an excellent liver stage P. berghei inhibitor (78: IC50 = 0.33 μM). Up to 91% reduction of the parasite liver load in mice was achieved at 100 mg/kg. Examination of tetraoxane 78 against the transgenic 3D7 strain expressing luciferase under a gametocyte-specific promoter revealed its activity against stage IV-V Plasmodium falciparum gametocytes (IC50 = 1.16 ± 0.37 μM). To the best of our knowledge, compounds 25 and 78 are the first examples of either an 4-aminoquinoline or a tetraoxane liver stage inhibitors.
- Terzi?, Natasa,Konstantinovi?, Jelena,Tot, Miklo?,Burojevi?, Jovana,Djurkovi?-Djakovi?, Olgica,Srbljanovi?, Jelena,?tajner, Tijana,Verbi?, Tatjana,Zlatovi?, Mario,Machado, Marta,Albuquerque, Inês S.,Prudêncio, Miguel,Sciotti, Richard J.,Pecic, Stevan,D'Alessandro, Sarah,Taramelli, Donatella,?olaja, Bogdan A.
-
supporting information
p. 264 - 281
(2016/01/29)
-
- GEMINAL SUBSTITUTED QUINUCLIDINE AMIDE COMPOUNDS AS AGONISTS OF ALPHA-7 NICOTINIC ACETYLCHOLINE RECEPTORS
-
The present invention relates to novel geminal substituted quinuclidine amide compounds, and pharmaceutical compositions of the same, that are suitable as agonists or partial agonists of α7- nAChR, and methods of preparing these compounds and compositions, and the use of these compounds and compositions in methods of maintaining, treating and/or improving cognitive function. In particular, methods of administering the compound or composition to a patient in need thereof, for example a patient with a cognitive deficiency and/or a desire to enhance cognitive function, that may derive a benefit therefrom.
- -
-
Paragraph 00285-00286
(2016/07/05)
-
- Structure-Activity Relationship Study of Heterocyclic Phenylethenyl and Pyridinylethenyl Derivatives as Tau-Imaging Agents That Selectively Detect Neurofibrillary Tangles in Alzheimers Disease Brains
-
In order to explore novel tau-imaging agents that can selectively detect neurofibrillary tangles in Alzheimers disease (AD) brains, we designed and synthesized a series of heterocyclic phenylethenyl and (3-pyridinyl)ethenyl derivatives with or without a dimethyl amino group. In in vitro autoradiography using AD brain sections, all radioiodinated ligands with a dimethyl amino group bound to Aβ deposits in the sections. In contrast, the ligands without a dimethyl amino group showed different patterns of radioactivity accumulation in the sections depending on the kind of heterocycle contained in their molecules. Particularly, a phenylethenyl benzimidazole derivative ([125I]64) showed marked radioactivity accumulation in the temporal lobe which corresponded with the distribution of tau deposits. [125I]64 also showed the most favorable pharmacokinetics in normal mouse brains (3.69 and 0.06% ID/g at 2 and 60 min postinjection, respectively) among all ligands in this study. Taken together, these results suggest that [123I]64 may be a new candidate tau-imaging agent.
- Matsumura, Kenji,Ono, Masahiro,Kitada, Ayane,Watanabe, Hiroyuki,Yoshimura, Masashi,Iikuni, Shimpei,Kimura, Hiroyuki,Okamoto, Yoko,Ihara, Masafumi,Saji, Hideo
-
p. 7241 - 7257
(2015/10/05)
-
- Radioactive iodine labeled compound, and, radioactive pharmaceutical containing the same (by machine translation)
-
PROBLEM TO BE SOLVED: and compatibility and affinity for both amyloidosis acryloyldimethyltauric, labeled compd. radioactive iodine. SOLUTION: the present invention, N, N-labeled compd. dimethyl benzene amine including radioactive iodine or its salt. Selected drawing: no (by machine translation)
- -
-
Paragraph 0016; 0047; 0048
(2018/10/10)
-
- Novel 2-Carbonylbenzo[b]thiophene 1,1-Dioxide Derivatives as Potent Inhibitors of STAT3 Signaling Pathway
-
Signal transducer and activator of transcription 3 (STAT3) is considered to be an attractive therapeutic target for cancer therapy. In this study, a series of 2-carbonylbenzo[b]thiophene 1,1-dioxide derivatives (CBT) were designed to inhibit the STAT3 SH2 domain phosphorylation site Try 705. We demonstrated that incorporation of basic flexible groups through amide bond linkage to benzo[b]thiophene 1,1-dioxide (BTP) achieved compounds with higher antiproliferative potency than BTP itself. The most potent compound 6o, as indicated from luciferase reporter gene assay, inhibited the STAT3 pathway by decreasing the phosphorylation level of STAT3 Tyr705, while the phosphorylation level of other upstream tyrosine kinases in this pathway was not significantly inhibited. Compound 6o was also shown to trigger ROS generation and accumulation, thus consequently attributed partially to the observed cell apoptosis. This study provided important structural information for the development of inhibitors targeting the STAT3 pathway.
- Ji, Peng,Xu, Xin,Ma, Shuhua,Fan, Junchao,Zhou, Qiang,Mao, Xinliang,Qiao, Chunhua
-
supporting information
p. 1010 - 1014
(2015/09/22)
-
- Synthesis of a ferrocene-functionalized unsymmetrical benzo[b]thienyl- thienylethene photoswitch with a cyclopentene core
-
A new and potentially general synthetic route toward unsymmetrical benzo[b]thienyl-thienylethene compounds is described, with specific focus on conjugation of a ferrocene to the benzo[b]thiophene subunit. The route proceeds in an overall yield of 17%. Copyright
- Zuckerman, Nathaniel B.,Kang, Xiongwu,Chen, Shaowei,Konopelski, Joseph P.
-
supporting information
p. 1482 - 1485
(2013/04/23)
-
- 17α-HYDROXYLASE/C17,20-LYASE INHIBITORS
-
The present invention provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5 and R6 are as defined herein. The compounds of the present invention have been found to be useful as 17α-hydroxylase/C17,20-lyase inhibitors.
- -
-
Page/Page column 58
(2012/11/13)
-
- COMPOUNDS AND METHODS FOR MODULATING FXR
-
Compounds of formula (I) wherein variables are as defined herein and their pharmaceutical compositions and methods of use are disclosed as useful for treating dyslipidemia and related diseases.
- -
-
Page/Page column 26-27
(2008/06/13)
-
- Discovery of a new series of potent and selective linear tachykinin NK 2 receptor antagonists
-
Starting from 1 (MEN 14268), a selective tachykinin NK2 receptor antagonist with an interesting in vitro pharmacological profile, a family of numerous antagonists was obtained through an optimization process focused on iterated structural modifications. The effects of the introduction of a wide variety of substituents on the lipophilic aromatic part of the molecule and the modulation of the structural constraint through the insertion of different achiral α,α-dialkylamino acids were investigated. In particular, aromatic and benzofused heteroaromatic moieties were introduced at the pseudo-N-terminal residue to replace the 2-benzothiophene moiety, and a systematic investigation of the best positioning of substituents onto the aromatic platform was reported for the benzothiophene core. Studies on the modulation of the length and the rigidity of the hydrophilic pseudo-C-terminal pendant are presented. Many heteroaliphatic groups are well tolerated by the receptor in this part of the ligand. The product 48f (MEN15596), bearing a methyl substituent on the benzothiophene and a tetrahydropyranylmethylpiperidine pendant, was finally selected for its good in vivo activity after intravenous, intraduodenal, and oral administration in guinea pigs.
- Fedi, Valentina,Altamura, Maria,Catalioto, Rose-Marie,Giannotti, Danilo,Giolitti, Alessandro,Giuliani, Sandro,Guidi, Antonio,Harmat, Nicholas J. S.,Lecci, Alessandro,Meini, Stefania,Nannicini, Rossano,Pasqui, Franco,Tramontana, Manuela,Triolo, Antonio,Maggi, Carlo Alberto
-
p. 4793 - 4807
(2008/03/12)
-
- Amides of acetic and propionic acids
-
The invention relates to novel amides of acetic and propionic acids, methods for production and use thereof for the production of medicaments for the treatment and/or prophylaxis of diseases and for improving perception, concentration, learning ability and memory.
- -
-
Page/Page column 7
(2008/06/13)
-
- COMPOUNDS AND METHODS FOR MODULATING FXR
-
Compounds of formula. wherein variables are as defined herein and their pharmaceutical compositions and methods of use are disclosed as useful for treating dyslipidemia and related diseases.
- -
-
Page/Page column 15
(2008/06/13)
-
- FXR AGONISTS
-
Compounds of formula wherein variables are as defined herein and their pharmaceutical compositions and methods of use are disclosed as useful for treating dyslipidemia and related diseases.
- -
-
Page/Page column 37
(2008/06/13)
-
- BENZOTHIOPHENE UREA, BENZOFURANE UREA, AND INDOLE UREA, AND USE OF THE SAME AS ALPHA-7 ACHR AGONISTS
-
The invention relates to novel benzothiophene urea, benzofurane urea, and indole urea, and to the use thereof for producing medicaments for the treatment and/or prophylaxis of diseases and for improving perception, concentration power, learning capacity and/or memory retention.
- -
-
Page/Page column 37-38
(2010/11/30)
-
- 2-HETEROARYL CARBOXAMIDES
-
The invention relates to the novel 2-heteroaryl carboxamides according to formula (I), wherein R1 represents 1-aza-bicyclo [2.2.2]oct-3-yl, which is optionally replaced via the nitrogen atom by a group selected from the family C1-C4 alkyl, benzyl and oxy, A represents oxygen or sulfur, the ring B represents benzo or pyrido that are optionally replaced by the groups from the family of halogen, cyano, formyl, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6 alkyl and C1-C6 alkoxy, E represents C=C, aryl and heteroaryl, wherein aryl and heteroaryl may be replaced by groups from the family of halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6 alkoxy and C1-C6 alkyl, and to the solvents, salts or solvents of salts of said compounds. The invention also relates to the use of said compounds in the production of drugs for the treatment and/or the prophylaxis of diseases and for improving perception, power of concentration, learning power and/or retentiveness of memory.
- -
-
-