- Triazole alcohol derivative as well as preparation method and application thereof
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The invention relates to a triazole alcohol derivative as well as a preparation method and application thereof. The chemical structure of the triazole alcohol derivative is shown as a formula I, R1 represents a benzene ring or a substituted benzene ring, and substituent groups of the substituted benzene ring can be located at all positions of the benzene ring, can be mono-substituted or multi-substituted, and can be selected from a) halogen which is F and Cl; b) an electron withdrawing group which is cyano or trifluoromethyl; c ) a lower alkyl of 1-4 carbon atoms or a halogen substituted loweralkyl; and d) lower alkoxy of 1-4 carbon atoms or halogen substituted lower alkoxy. The compound of the invention has strong antifungal activity, has the advantages of low toxicity, wide antibacterial spectrum and the like, and can be used for preparing antifungal drugs.
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Paragraph 0203-0204
(2020/03/11)
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- Design, synthesis, and in vitro evaluation of novel triazole analogues featuring isoxazole moieties as antifungal agents
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In order to develop novel antifungal agents, based on our previous work, a series of (2R,3R)-3-((3-substitutied-isoxazol-5-yl)methoxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol (a1-a26) were designed and synthesized. All of the compounds exhibited good in vitro antifungal activities against eight human pathogenic fungi. Among them, compound a6 showed excellent inhibitory activity against Candida albicans and Candida parasilosis with MIC80 values of 0.0313 μg/mL. In addition, compounds a6, a9, a12, a13 and a14 exhibited moderate inhibitory activities against fluconazole-resistant isolates with MIC80 values ranging from 8 μg/mL to 16 μg/mL. Furthermore, compounds a6, a12 and a23 exhibited low inhibition profiles for CYP3A4. Clear SARs were analyzed, and the molecular docking experiment was carried out to further investigate the relationship between a6 and the target enzyme CYP51.
- Chai, Xiaoyun,Ding, Zichao,Hao, Yumeng,Jiang, Yuanying,Jin, Yongsheng,Ni, Tingjunhong,Wang, Ruilian,Wang, Ruina,Wang, Ting,Xie, Fei,Yu, Shichong,Zhang, Dazhi
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supporting information
(2020/06/17)
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- FXR receptor agonist
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The present invention discloses an FXR receptor agonist, belongs to the technical field of medicine, and particularly relates to a compound represented by a formula (I), a pharmaceutically acceptablesalt, an ester or a stereoisomer thereof, wherein R, R, R, M, L, L1, W, A , B, Q, m and n are defined in the specification. The present invention further relates to a preparation method of the compound, a pharmaceutical preparation, and applications in preparation of drugs for treatment and/or prevention of nonalcoholic fatty liver disease, primary biliary cirrhosis, lipid metabolism disorder, diabetic complication, malignant tumors and other related diseases mediated by FXR receptors. The formula I is defined in the specification.
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Paragraph 0391; 0393; 0394; 0395
(2019/02/10)
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- Design, synthesis, and in vitro evaluation of novel antifungal triazoles
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Twenty-nine novel triazole analogues of ravuconazole and isavuconazole were designed and synthesized. Most of the compounds exhibited potent in vitro antifungal activities against 8 fungal isolates. Especially, compounds a10, a13, and a14 exhibited superior or comparable antifungal activity to ravuconazole against all the tested fungi. Structure-activity relationship study indicated that replacing 4-cyanophenylthioazole moiety of ravuconazole with fluorophenylisoxazole resulted in novel antifungal triazoles with more effectiveness and a broader-spectrum.
- Xie, Fei,Ni, Tingjunhong,Zhao, Jing,Pang, Lei,Li, Ran,Cai, Zhan,Ding, Zichao,Wang, Ting,Yu, Shichong,Jin, Yongsheng,Zhang, Dazhi,Jiang, Yuanying
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supporting information
p. 2171 - 2173
(2017/04/28)
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- Triazole alcohol derivative and preparation method and application thereof
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The invention relates to a triazole alcohol derivative and a preparation method and application thereof. The chemical structure of the triazole alcohol derivative is as shown in the formula I. The invention also provides salt of the compound, a pharmaceutical composition, a preparation method and application. The compound of the invention has strong antifungal activity, has advantages of low toxicity and wide antimicrobial spectrum, and can be used for preparation of antifungal drugs.
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Paragraph 0247; 0295
(2017/06/28)
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- Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH)
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The farnesoid X receptor (FXR) is a nuclear receptor that acts as a master regulator of bile acid metabolism and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and nonalcoholic steatohepatitis. We identified a novel series of highly potent non-bile acid FXR agonists that introduce a bicyclic nortropine-substituted benzothiazole carboxylic acid moiety onto a trisubstituted isoxazole scaffold. Herein, we report the discovery of 1 (tropifexor, LJN452), a novel and highly potent agonist of FXR. Potent in vivo activity was demonstrated in rodent PD models by measuring the induction of FXR target genes in various tissues. Tropifexor has advanced into phase 2 human clinical trials in patients with NASH and PBC.
- Tully, David C.,Rucker, Paul V.,Chianelli, Donatella,Williams, Jennifer,Vidal, Agnès,Alper, Phil B.,Mutnick, Daniel,Bursulaya, Badry,Schmeits, James,Wu, Xiangdong,Bao, Dingjiu,Zoll, Jocelyn,Kim, Young,Groessl, Todd,McNamara, Peter,Seidel, H. Martin,Molteni, Valentina,Liu, Bo,Phimister, Andrew,Joseph, Sean B.,Laffitte, Bryan
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supporting information
p. 9960 - 9973
(2018/01/11)
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- AMINOBENZISOXAZOLE COMPOUNDS AS AGONISTS OF A7-NICOTINIC ACETYLCHOLINE RECEPTORS
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The present invention relates to novel aminobenzisoxazole compounds, and pharmaceutical compositions of the same, that are suitable as agonists or partial agonists of ot7-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.
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Paragraph 00187-00188; 00254-00255
(2017/01/31)
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- Design, Synthesis, and Biological Evaluation of Novel Nonsteroidal Farnesoid X Receptor (FXR) Antagonists: Molecular Basis of FXR Antagonism
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Farnesoid X receptor (FXR) plays an important role in the regulation of cholesterol, lipid, and glucose metabolism. Recently, several studies on the molecular basis of FXR antagonism have been reported. However, none of these studies employs an FXR antagonist with nonsteroidal scaffold. On the basis of our previously reported FXR antagonist with a trisubstituted isoxazole scaffold, a novel nonsteroidal FXR ligand was designed and used as a lead for structural modification. In total, 39 new trisubstituted isoxazole derivatives were designed and synthesized, which led to pharmacological profiles ranging from agonist to antagonist toward FXR. Notably, compound 5s (4′-[(3-{[3-(2-chlorophenyl)-5-(2-thienyl)isoxazol-4-yl]methoxy}-1H-pyrazol-1-yl)methyl]biphenyl-2-carboxylic acid), containing a thienyl-substituted isoxazole ring, displayed the best antagonistic activity against FXR with good cellular potency (IC50=12.2±0.2μM). Eventually, this compound was used as a probe in a molecular dynamics simulation assay. Our results allowed us to propose an essential molecular basis for FXR antagonism, which is consistent with a previously reported antagonistic mechanism; furthermore, E467 on H12 was found to be a hot-spot residue and may be important for the future design of nonsteroidal antagonists of FXR. X marks the spot: 39 trisubstituted isoxazoles were designed and synthesized, leading to compounds with pharmacological profiles ranging from agonist to antagonist at the farnesoid X receptor (FXR). By using the most potent antagonist as a probe, the essential molecular basis of FXR antagonism is proposed, and E467 on H12 can be regarded as a hot-spot residue for the future design of nonsteroidal antagonists of FXR.
- Huang, Huang,Si, Pei,Wang, Lei,Xu, Yong,Xu, Xin,Zhu, Jin,Jiang, Hualiang,Li, Weihua,Chen, Lili,Li, Jian
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p. 1184 - 1199
(2015/07/07)
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- Oxime Carbamate-Discovery of a series of novel FAAH inhibitors
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A series of novel oxime carbamates have been identified as potent inhibitors of the key regulatory enzyme of the endocannabinoid signaling system, fatty acid amide hydrolase (FAAH). In this Letter, the rationale behind the discovery and the biological evaluations of this novel class of FAAH inhibitors are presented. Both in vitro and in vivo results of selected targets are discussed, along with inhibition kinetics and molecular modeling studies.1.
- Sit,Conway, Charles M.,Xie, Kai,Bertekap, Robert,Bourin, Clotilde,Burris, Kevin D.
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supporting information; experimental part
p. 1272 - 1277
(2010/06/17)
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- Biologically active hydroxymoyl chlorides as antifungal agents
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Several oximes and oxime ethers have been developed as antimicrobial agents. A series of chlorooximes (hydroximoyl chlorides) have been synthesized and tested for antifungal activity under in-vitro conditions against Candida albicans, Candida parapsilosis, Candida glabrata, Candida krusei, Aspergillus fumigatus, Aspergilhis flaviis and Aspergillus niger. The derived antifungal activity has been compared with the corresponding oximes. The results show that most of the chlorooximes exhibit potent antifungal activity with anti-isomers showing better activity. It is observed that most of the chlorooximes show interesting antifungal activity (MICs ≤ 32 μg/mL) compared to oximes. Compound 3q (2,3-dimethoxy phenyl hydroxymoyl chloride) is the most active compound. This compound is active against all the Candida species (MIC 0.5 μg/mL) as well as filamentous fungi with MIC range of 2-4 μg/mL. This series of compounds are fungicidal in nature as evident from the MFC results.
- Ismail, Tabasum,Shafi, Syed,Singh, Parvinder Pal,Qazi, Naveed Ahmed,Sawant, Sanghapal D.,Ali, Intzar,Khan, Inshad Ali,Kumar,Qazi, Ghulam Nabi,Alam, M. Sarwar
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p. 740 - 747
(2008/12/20)
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- Potent inhibitors of lipoprotein-associated phospholipase A2: Benzaldehyde O-heterocycle-4-carbonyloxime
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A series of multi-substituted oximes were prepared and their potencies for inhibiting lipoprotein-associated phospholipase A2 (Lp-PLA2) activity were evaluated in vitro. Among them, compounds 3a, 3b, and 3m were identified to display a micromolar potency for inhibiting Lp-PLA2 in whole human plasma and isolated human LDL. Based on these results, structure-activity relationship was studied on modification of three parts of R1, R2, and R3 to identify a potent pharmacophore for Lp-PLA2. In an attempt to introduce various functional groups at R2 and R3, we discovered that replacement of less lipophilic groups led to an increase of inhibitory activity. Among the tested oxime derivatives, cyano- and morpholino-substituted analogue 4f at R2 and R3 had the highest potency with an IC50 value of 0.05 μM in whole human plasma.
- Jeong, Hyung Jae,Park, Yong-Dae,Park, Ho-Yong,Jeong, Il Yun,Jeong, Tae-Sook,Lee, Woo Song
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p. 5576 - 5579
(2007/10/03)
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- Compounds and method for inhibiting MRP1
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The present invention relates to a compound of formula (I), which is useful for inhibiting resistant neoplasms where the resistance is conferred in part or in total by MRP1.
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Page column 43
(2010/02/05)
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- Ozonolysis of Alkenes and Studies of the Reactions of Polyfunctional Compounds. LVIII. Ozonolysis of 2,6-Difluoro-β,β-Dimethylstyrene as an Effective Way to 2,6-Difluorobenzamide and Synthesis of New Analogs of Difluorobenzurone
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Ozonolysis of 2,6-difluoro-β,β-dimethylstyrene, formed by isomerization of the product of alkylation of sodium derivative of m-difluorobenzene with methallyl chloride, yields 2,6-difluorobenzamide, transformation of which to 2,6-difluorobenzoyl isocyanate and the reaction of the latter with corresponding arylamines leads to new effective analogs of difluorobenzurone.
- Odinokov,Ishmuratov,Kukovinets,Harisov,Lozhkina,Mustafin,Abdrahmanov,Tolstikov
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p. 202 - 204
(2007/10/03)
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