- Design, synthesis, biological evaluation and in silico study of benzyloxybenzaldehyde derivatives as selective aldh1a3 inhibitors
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Aldehyde dehydrogenase 1A3 (ALDH1A3) has recently gained attention from researchers in the cancer field. Several studies have reported ALDH1A3 overexpression in different cancer types, which has been found to correlate with poor treatment recovery. Theref
- Ibrahim, Ali I. M.,Ikhmais, Balqis,Batlle, Elisabet,Abuharb, Waed K.,Jha, Vibhu,Jaradat, Khaled T.,Jiménez, Rafael,Pequerul, Raquel,Parés, Xavier,Farrés, Jaume,Pors, Klaus
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- Evolution of a 4-Benzyloxy-benzylamino Chemotype to Provide Efficacious, Potent, and Isoform Selective PPARα Agonists as Leads for Retinal Disorders
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Peroxisome proliferator-activated receptor alpha (PPARα) is expressed in retinal Müller cells, endothelial cells, and in retinal pigment epithelium; agonism of PPARα with genetic or pharmacological tools ameliorates inflammation, vascular leakage, neurodegeneration, and neovascularization associated with retinal diseases in animal models. As such, PPARα is a promising drug target for diabetic retinopathy and age-related macular degeneration. Herein, we report proof-of-concept in vivo efficacy in an streptozotocin-induced vascular leakage model (rat) and preliminary pharmacokinetic assessment of a first-generation lead 4a (A91). Additionally, we present the design, synthesis, and evaluation of second-generation analogues, which led to the discovery of 4u and related compounds that reach cellular potencies 2,700-fold selectivity for PPARα over other PPAR isoforms. These studies identify a pipeline of candidates positioned for detailed PK/PD and pre-clinical evaluation.
- Dou, Xiaozheng,Nath, Dinesh,Shin, Henry,Nurmemmedov, Elmar,Bourne, Philip C.,Ma, Jian-Xing,Duerfeldt, Adam S.
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p. 2854 - 2876
(2020/04/10)
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- Synthesis and biological evaluation of tryptophan-derived rhodanine derivatives as PTP1B inhibitors and anti-bacterial agents
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Several series of novel tryptophan-derived rhodanine derivatives were synthesized and identified as potential competitive PTP1B inhibitors and antibacterial agents. Among the compounds studied, 10b was found to have the best in vitro inhibition activity against PTP1B (IC50 = 0.36 ± 0.02 μM). In addition, the compounds also showed potent inhibition against other PTPs, especially CDC25B. Molecular docking analysis demonstrated that compounds 7c and 10b could occupy both the catalytic site and the adjacent pTyr binding site simultaneously. The compounds also showed higher levels of activity against gram-positive strains, the gram-negative strain Escherichia coli 1924, and multidrug-resistant gram-positive bacterial strains. Compounds 7c, 8c, 9e, 10a, and 10c had comparable or more potent antibacterial activity than the positive controls.
- Liu, Hongyan,Sun, Danwen,Du, Hang,Zheng, Changji,Li, Jingya,Piao, Huri,Li, Jia,Sun, Liangpeng
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p. 163 - 173
(2019/04/13)
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- Novel cinnamic acid–tryptamine hybrids as potent butyrylcholinesterase inhibitors: Synthesis, biological evaluation, and docking study
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A novel series of cinnamic acid–tryptamine hybrids was designed, synthesized, and evaluated as cholinesterase inhibitors. Anticholinesterase assays showed that all of the synthesized compounds displayed a clearly selective inhibition of butyrylcholinesterase (BChE), but only a moderate inhibitory effect toward acetylcholinesterase (AChE) was detected. Among these cinnamic acid–tryptamine hybrids, compound 7d was found to be the most potent inhibitor of BChE with an IC50 value of 0.55 ± 0.04 μM. This compound showed a 14-fold higher inhibitory potency than the standard drug donepezil (IC50 = 7.79 ± 0.81 μM) and inhibited BChE through a mixed-type inhibition mode. Moreover, a docking study revealed that compound 7d binds to both the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of BChE. Also, compound 7d was evaluated against β-secretase, which exhibited low activity (inhibition percentage: 38%).
- Ghafary, Shahrzad,Najafi, Zahra,Mohammadi-Khanaposhtani, Maryam,Nadri, Hamid,Edraki, Najmeh,Ayashi, Neda,Larijani, Bagher,Amini, Mohsen,Mahdavi, Mohammad
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- An eco-friendly synthesis of 4-aryl-substituted pyrano-fuzed coumarins as potential pharmacological active heterocycles using molybdenum oxide nanoparticles as an effective and recyclable catalyst
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A green cascade three-component reaction between 4-hydroxycoumarin, malononitrile and a wide range of arylaldehydes by employing molybdenum oxide nanoparticles (MoO3 NPs) is described. By this achievement, some medicinally important products have been successfully synthesized in a one-pot under green conditions. Obtaining good to excellent yields of products, environmentally benign procedure, being easily handled, availability of starting materials, use of non-toxic solvents, and high recyclability of nano-catalysts are the most important advantages of this methodology.
- Pourshojaei, Yaghoub,Jadidi, Mohammad-Hossein,Eskandari, Khalil,Foroumadi, Alireza,Asadipour, Ali
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p. 4195 - 4212
(2018/03/21)
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- Ultrasound-assisted and efficient knoevenagel condensation reaction catalyzed by silica sodium carbonate nanoparticles
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An efficient and ultrasound-assisted route to the synthesis of arylidene malononitriles/methylciano- or ethylciano acetates in a one-pot reaction catalyzed by silica sodium carbonate nanoparticles (SSC NPs) is described. In this reaction, SSC NPs demonstrated high efficiency as catalyst to obtain target products. By this achievement, a wide range of α,β-unsaturated compounds as Knoevenagel condensation products with good to excellent yields are obtained from reaction between numerous arylaldehydes, and malononitrile, methyl cianoacetate or ethyl cianoacetate. Target products which prepared in high yield and high purity can be candidate as important biologically active molecules. This method is an easy, cheap, rapid and highly efficient for the synthesis of desired products. In addition, capability of catalyst to separate from reaction mixture and reuse in further runs and being compatible with green chemistry are considered as other advantages of this procedure. All products were deduced from their FT-IR and FT-NMR spectroscopic and elemental analysis data.
- Pourshojaei, Yaghoub,Nikzad, Maryam,Eskandari, Khalil,Darijani, Mohammad-Hossein,Hassanzadeh, Abdolreza,Faghih-Mirzaei, Ehsan,Asadipour, Ali
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- Sophoridine pyrrole, indole derivative and preparation method and application thereof
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The invention relates to a sophoridine pyrrole, indole derivative. The invention discloses a chemical structure of the compound and further discloses a preparation method of the compound. In vitro anti-tumor activity researches show that anti-tumor drugs
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Paragraph 0191; 0193; 0195; 0204
(2018/09/08)
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- Nitrogen-containing heterocyclic amide derivative and use thereof
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The present invention discloses a nitrogen-containing heterocyclic amide derivative and use thereof, and in particular, the present invention relates to a novel class of nitrogen-containing heterocyclic amide derivatives and pharmaceutical compositions co
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Paragraph 0256-0257; 0342; 0344-0345
(2019/01/06)
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- Structure-guided evolution of a 2-phenyl-4-carboxyquinoline chemotype into PPARα selective agonists: New leads for oculovascular conditions
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Small molecule agonism of PPARα represents a promising new avenue for the development of non-invasive treatments for oculovascular diseases like diabetic retinopathy and age-related macular degeneration. Herein we report initial structure–activity relatio
- Dou, Xiao-Zheng,Nath, Dinesh,Shin, Younghwa,Ma, Jian-Xing,Duerfeldt, Adam S.
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supporting information
p. 2717 - 2722
(2018/03/23)
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- Synthesis and biological evaluation of dihydrotriazine derivatives as potential antibacterial agents
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A series of 1,4-dihydro-1,3,5-triazine derivatives were designed and synthesized and their antibacterial and antifungal activities were evaluated. Most of the synthesized compounds showed potent inhibition of several Gram-positive bacterial strains (including multidrug-resistant clinical isolates) and Gram-negative bacterial strains, with minimum inhibitory concentrations (MICs) in the range of 2.1–181.2?μmol/L. Compounds 7a and 7c presented the most potent inhibitory activities against Gram-positive bacteria (e.g., Staphylococcus aureus 4220), Gram-negative bacteria (e.g., Escherichia coli 1924), and the fungus Candida albicans 7535, with MICs of 2.1 or 4.1?μmol/L. Especially, compound 7a was the most potent, with an MIC of 2.1?μmol/L against four multidrug-resistant, Gram-positive bacterial strains. The cytotoxic activity of the compound 7a, 7c and 7f was assessed in HepG2 cells, and the results suggest that 1,4-dihydro-1,3,5-triazine derivatives bearing a 6-benzyloxynaphthalen moiety are interesting scaffolds for the development of novel antibacterial agents.
- Zhang, Tian-Yi,Li, Chao,Tian, Yu-Shun,Li, Jia-Jun,Sun, Liang-Peng,Zheng, Chang-Ji,Piao, Hu-Ri
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supporting information
p. 1737 - 1742
(2017/07/27)
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- Phenolic compounds containing benzyloxy phenyl and preparation method and application of phenolic compounds
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The invention discloses phenolic compounds (I) containing benzyloxy phenyl and a preparation method and application of the phenolic compounds. Pharmacological experiments prove that the phenolic compounds have high inhibiting activity on sphingosine kinase SphK, and part of the compounds has a certain inhibiting effect on inflammatory bowel disease induced by tumor and DSS. The phenolic compounds and the pharmaceutical preparations thereof can be used for preparing drugs for treating a series of cancer and inflammatory diseases such as colon cancer, lung cancer, breast cancer, liver cancer, stomach cancer, inflammatory bowel disease, hepatitis, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis and multiple sclerosis.
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Paragraph 0406-0410
(2017/09/19)
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- Synthesis and analysis of anticonvulsant activities of new 4-[2-(4-alkoxybenzylamino)ethyl]-2H-1,2,4-triazol-3(4H)-one derivatives
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The present study involved the design and synthesis of new substituted 4-[2-(4-alkoxybenzylamino) ethyl]-2H-1,2,4-triazol-3(4H)-one derivatives (8a-w) starting from 1,2-ethanediamine. The final compounds were screened for their in vivo anticonvulsant activities and neurotoxicities by maximal electroshock (MES) and rotarod tests, respectively. Among the compounds studied, 4-[2-(4-butoxybenzylamino)ethyl]-2H-1,2,4-triazol-3(4H)-one hydrochloride (8b) was found by intraperitoneal administration in mice to be the most potent compound with a median effective dose (ED50) value of 33.2 mg/kg and a high protective index (PI) value of 11.4. Compound 8b showed significant oral activity against MES-induced seizures in mice with an ED50 value of 83.1 mg/kg and a PI of 18.1. The results demonstrated that compound 8b possessed better anticonvulsant activity and higher safety than the marketed drug carbamazepine.
- Shen, Qing-Kun,Wang, Shi-Ben,Gong, Guo-Hua,Yin, Xiu-Mei,Quan, Zhe-Shan
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p. 430 - 438
(2015/06/22)
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- Vanillin-derived antiproliferative compounds influence Plk1 activity
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We synthesized a series of vanillin-derived compounds and analyzed them in HeLa cells for their effects on the proliferation of cancer cells. The molecules are derivatives of the lead compound SBE13, a potent inhibitor of the inactive conformation of huma
- Carrasco-Gomez, Roberto,Keppner-Witter, Sarah,Hieke, Martina,Lange, Lisa,Schneider, Gisbert,Schubert-Zsilavecz, Manfred,Proschak, Ewgenij,Sp?nkuch, Birgit
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supporting information
p. 5063 - 5069
(2014/12/11)
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- Synthesis and antimicrobial evaluation of L-phenylalanine-derived C5-substituted rhodanine and chalcone derivatives containing thiobarbituric acid or 2-thioxo-4-thiazolidinone
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Four novel series of compounds, including the l-phenylalanine-derived C5-substituted rhodanine (6a-q, 7a-j) and chalcone derivatives containing thiobarbituric acid or 2-thioxo-4-thiazolidinone (9a-e, 11a-e) have been designed, synthesized, characterized, and evaluated for their antibacterial activity. Some of these compounds showed significant antibacterial activity against Gram-positive bacterias, especially against the strains of multidrug-resistant clinical isolates, among which compounds 6c-e, 6g, 6i, 6j and 6q exhibiting high levels of antimicrobial activity against Staphylococcus aureus RN4220 with minimum inhibitory concentration (MIC) values of 2 μg/mL. Compound 6q showed the most potent activity of all of the compounds against all of the test multidrug-resistant clinical isolates tested. Unfortunately, however, none of the compounds were active against Gram-negative bacteria at 64 μg/mL.
- Zheng, Chang-Ji,Song, Ming-Xia,Wu, Yan,Sun, Liang-Peng,Li, Yin-Jing,Piao, Hu-Ri,Jin, Xin,Yu, Li-Jun
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p. 203 - 209,7
(2012/12/12)
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- Isoxazol-5(4H)one derivatives as PTP1B inhibitors showing an anti-obesity effect
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In developing inhibitors of therapeutic target enzymes, significant time and effort are committed to the preparation of large numbers of compounds. In an effort to develop a potent inhibitor of protein tyrosine phosphatase (PTP) 1B as an anti-obesity and/or anti-diabetic agent, we constructed an isoxazolone chemical library by using a simplified procedure that circumvents tedious workup and purification steps. The 10× 7 isoxazolone derivatives were synthesized by coupling the two halves of the target compounds. When mixed and heated in test tubes, the precursors produced the reaction products as precipitates. After brief washing, the products were pure enough to be used for enzymatic experiments. With the precursors for the coupling reactions prepared, the 10× 7 library compounds could be prepared in a day by using the present protocol. The library compounds thus obtained were examined for their inhibitory activities against PTP1B. Among them, compound C3 was the most potent inhibitor of PTP1B with an IC50 of 2.3 μM. The in vivo effect of C3 was also examined in an obesity-prone mouse strain. Diet-induced obese (DIO)/diabetic mice were divided into two groups and each group was fed a high-fat diet (HFD) or HFD+C3 for four weeks. The group of C3-fed mice gained significantly less weight relative to the HFD-fed control group during the four weeks of the drug feeding period. In contrast to the anti-obesity effect of C3, no difference was observed in the glycemic control of the HFD and HFD+C3 mice groups.
- Kafle, Bhooshan,Aher, Nilkanth G.,Khadka, Deegendra,Park, Hwangseo,Cho, Hyeongjin
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supporting information; experimental part
p. 2073 - 2079
(2011/11/05)
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- NOVEL PROTEIN TYROSINE PHOSPHATASE - IB INHIBITORS
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The present invention relates to the novel compounds of the general formula (I), wherein the symbols are same as described in specification, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, to process and intermediates for the preparation of the above said compounds, having the utility of these compounds in medicine and to methods for their therapeutic use, and their use in the treatment of metabolic disorders.
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Page/Page column 75
(2009/10/22)
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- Selective and potent monoamine oxidase type B inhibitors: substituted semicarbazones and acylhydrazones of aromatic aldehydes and ketones
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The synthesis and the evaluation of the monoamine oxidase A and B inhibitory activities of 21 new substituted acylhydrazones of various aromatic aldehydes and 4-(benzyloxy)acetophenone, and four substituted semicarbazones of benzaldehyde and 4-(benzyloxy)benzaldehyde, are described.The 4-(benzyloxy)phenyl group contributing to a high lipophilicity led to the most active compounds.One of these, compound 3g (IC50 = 3 nM, MAO A/MAO B selectivity > 33 000), was found to act as a revervible and probably tight-binding inhibitor.The studied acyclic hydrazones and semicarbazones are structurally related to other reversible and potent inhibitors, eg, heterocyclic compounds such as 1,3,4-oxadiazol-2(3H)-one derivatives in which the hydrazono group is intracyclic.Some of these new inhibitors might find use in the symptomatic treatment of neurodegenerative processes.MAO B inhibitor / hydrazone (aromatic acyl-) / semicarbazone (aromatic)
- Bernard, S.,Paillat, C.,Oddos, T.,Seman, M.,Milcent, R.
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p. 471 - 482
(2007/10/02)
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