- Cyanopyridyl containing 1,4-dihydroindeno[1,2-c]pyrazoles as potent checkpoint kinase 1 inhibitors: Improving oral biovailability
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A series of 1,4-dihydroindeno[1,2-c]pyrazole compounds with a cyanopyridine moiety at the 3-position of the tricyclic pyrazole core was explored as potent CHK-1 inhibitors. The impact of substitutions at the 6 and/or 7-position of the core on pharmacokinetic properties was studied in detail. Compounds carrying a side chain with an ether linker at the 7-position and a terminal morpholino group, such as 29 and 30, exhibited much-improved oral biovailability in mice as compared to earlier generation inhibitors. These compounds also possessed desirable cellular activity in potentiating doxorubicin and will serve as valuable tool compounds for in vivo evaluation of CHK-1 inhibitors to sensitize DNA-damaging agents.
- Tong, Yunsong,Przytulinska, Magdalena,Tao, Zhi-Fu,Bouska, Jennifer,Stewart, Kent D.,Park, Chang,Li, Gaoquan,Claiborne, Akiyo,Kovar, Peter,Chen, Zehan,Merta, Philip J.,Bui, Mai-Ha,Olson, Amanda,Osterling, Donald,Zhang, Haiying,Sham, Hing L.,Rosenberg, Saul H.,Sowin, Thomas J.,Lin, Nan-horng
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Read Online
- Synthesis, characterization and nonlinear optical studies of novel blue-light emitting room temperature truxene discotic liquid crystals
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A new series of discotic liquid crystals based on a truxene core has been synthesized to study the structure-property relationship in view of the self-assembling property and their linear and nonlinear optical properties. All these branched alkyl chain truxene derivatives show a mesogenic property in a columnar hexagonal fashion at room temperature which is studied by a combination of different techniques. The newly synthesized truxene discotic 7a possesses a clearing temperature of 117 °C, one of the lowest clearing temperatures known in truxene discotic liquid crystals. We have discovered that the introduction of branching near to the core even in a small alkyl chain drastically reduces the isotropic temperature. Due to their C3 symmetry and their large first hyperpolarizability, these truxene derivatives show long-lived emissions in the solution state at room temperature. We also report large effective three-photon absorption in these materials under nanosecond laser pulse excitation at 532 nm, which makes them suitable candidates for optical limiting applications.
- Vinayakumara,Kumar, Manish,Sreekanth,Philip, Reji,Kumar, Sandeep
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Read Online
- Efficient demethylation of aromatic methyl ethers with HCl in water
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A green, efficient and cheap demethylation reaction of aromatic methyl ethers with mineral acid (HCl or H2SO4) as a catalyst in high temperature pressurized water provided the corresponding aromatic alcohols (phenols, catechols, pyrogallols) in high yield. 4-Propylguaiacol was chosen as a model, given the various applications of the 4-propylcatechol reaction product. This demethylation reaction could be easily scaled and biorenewable 4-propylguaiacol from wood and clove oil could also be applied as a feedstock. Greenness of the developed methodversusstate-of-the-art demethylation reactions was assessed by performing a quantitative and qualitative Green Metrics analysis. Versatility of the method was shown on a variety of aromatic methyl ethers containing (biorenewable) substrates, yielding up to 99% of the corresponding aromatic alcohols, in most cases just requiring simple extraction as work-up.
- Bomon, Jeroen,Bal, Mathias,Achar, Tapas Kumar,Sergeyev, Sergey,Wu, Xian,Wambacq, Ben,Lemière, Filip,Sels, Bert F.,Maes, Bert U. W.
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p. 1995 - 2009
(2021/03/26)
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- Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate
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The acetylcholinesterase (AChE) inhibitors remain key therapeutic drugs for the treatment of Alzheimer's disease (AD). However, the low-safety window limits their maximum therapeutic benefits. Here, a novel kinetics-driven drug design strategy was employed to discover new-generation AChE inhibitors that possess a longer drug-target residence time and exhibit a larger safety window. After detailed investigations, compound 12 was identified as a highly potent, highly selective, orally bioavailable, and brain preferentially distributed AChE inhibitor. Moreover, it significantly ameliorated cognitive impairments in different mouse models with a lower effective dose than donepezil. The X-ray structure of the cocrystal complex provided a precise binding mode between 12 and AChE. Besides, the data from the phase I trials demonstrated that 12 had good safety, tolerance, and pharmacokinetic profiles at all preset doses in healthy volunteers, providing a solid basis for its further investigation in phase II trials for the treatment of AD.
- Zhou, Yu,Fu, Yan,Yin, Wanchao,Li, Jian,Wang, Wei,Bai, Fang,Xu, Shengtao,Gong, Qi,Peng, Tao,Hong, Yu,Zhang, Dong,Zhang, Dan,Liu, Qiufeng,Xu, Yechun,Xu, H. Eric,Zhang, Haiyan,Jiang, Hualiang,Liu, Hong
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p. 1844 - 1855
(2021/03/01)
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- Indanone derivative 5,6-dyhydroxy-2,3-dihydrocaroone-1H-indene-1-ketone and preparation method thereof
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The invention provides indanone derivative 5,6-dyhydroxy-2,3-dihydrocaroone-1H-indene-1-ketone and a preparation method thereof, relates to indanone derivatives and a preparation method thereof and aims to solve the technical problems that in the prior art, the operation process is complex, controllability is poor, the product yield is low, and stability is poor. The structural formula of the indanone derivative can be found in the specification. The preparation method includes the steps that 1, a 5,6-dimethoxy-2,3-dihydrocaroone-1H-indene-1-ketone solution is prepared; 2, boron tribromide is added for a reaction; 3, a saturated sodium bicarbonate solution is added for neutralizing the boron tribromide; 4, extraction and spin steaming are conducted. A product obtained through the method has good stability and a high yield; by means of the method, two methoxyl functional groups adjacent to indanone are converted into hydroxyl, and the activity of the indanone is greatly improved so that indanone derivatives provided with different substituent groups can be synthesized on the indanone, and crystal complexes of different spacial structures are configured. The preparation method is used for preparing the 5,6-dyhydroxy-2,3-dihydrocaroone-1H-indene-1-ketone.
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Paragraph 0038-0047
(2016/11/28)
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- Multitarget-directed benzylideneindanone derivatives: Anti-β-amyloid (Aβ) aggregation, antioxidant, metal chelation, and monoamine oxidase B (MAO-B) inhibition properties against Alzheimer's disease
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A novel series of benzylideneindanone derivatives were designed, synthesized, and evaluated as multitarget-directed ligands against Alzheimer's disease. The in vitro studies showed that most of the molecules exhibited a significant ability to inhibit self-induced β-amyloid (Aβ 1-42) aggregation (10.5-80.1%, 20 μM) and MAO-B activity (IC 50 of 7.5-40.5 μM), to act as potential antioxidants (ORAC-FL value of 2.75-9.37), and to function as metal chelators. In particular, compound 41 had the greatest ability to inhibit Aβ1-42 aggregation (80.1%), and MAO-B (IC50 = 7.5 μM) was also an excellent antioxidant and metal chelator. Moreover, it is capable of inhibiting Cu(II)-induced Aβ1-42 aggregation and disassembling the well-structured Aβ fibrils. These results indicated that compound 41 is an excellent multifunctional agent for the treatment of AD.
- Huang, Ling,Lu, Chuanjun,Sun, Yang,Mao, Fei,Luo, Zonghua,Su, Tao,Jiang, Huailei,Shan, Wenjun,Li, Xingshu
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p. 8483 - 8492,10
(2020/09/15)
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- INDANONE INHIBITORS OF ACETYLCHOLINESTERASE
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The present invention relates to new indanone inhibitors of acetylcholinesterase, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 16
(2010/06/19)
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- Synthesis and biological evaluation of 4′-(6,7-disubstituted-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-biphenyl-4-ol as potent Chk1 inhibitors
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A new series of potent tricyclic pyrazole-based Chk1 inhibitors are described. Analogues disubstituted on the 6- and 7-positions show improved Chk1 inhibition potency compared with analogues with a single substituent on either the 6- or 7-position. Based
- Tao, Zhi-Fu,Li, Gaoquan,Tong, Yunsong,Chen, Zehan,Merta, Philip,Kovar, Peter,Zhang, Haiying,Rosenberg, Saul H.,Sham, Hing L.,Sowin, Thomas J.,Lin, Nan-Horng
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p. 4308 - 4315
(2008/02/09)
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- Simple and regioselective bromination of 5,6-disubstituted-indan-1-ones with Br2 under acidic and basic conditions
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Bromination of 5,6-dimethoxyindan-1-one with Br2 in acetic acid at room temperature produced exclusively the corresponding 2,4-dibromo compound in 95% yield. Reaction of 5,6-dimethoxyindan-1-one with Br2 in the presence of KOH, K2CO3 or Cs2CO3 at ～0°C gave the monobrominated product 4-bromo-5,6-dimethoxyindan-3-one in 79%, 81% and 67% yield, respectively. 5,6-Dihydroxyindan-1-one was dibrominated on the aromatic ring affording 4,7-dibromo-5,6-dihydroxyindan-1-one both in acetic acid at room temperature and in the presence of KOH at ～0° C. 5,6-Difluoroindan-1-one and 1-indanone were α-monobrominated in acetic acid and α,aα-dibrominated under KOH conditions at room temperature.
- Choi, Taeyoung,Ma, Eunsook
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- Synthesis and biological evaluation of a novel series of "ortho-nitrated" inhibitors of catechol-O-methyltransferase
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Novel regioisomeric "ortho-nitrated" catechols related to the catechol-O-methyltransferase (COMT) inhibitors BIA 3-202 3 and BIA 3-335 4 were synthesized and biologically evaluated. Changing the position of the nitro group from the "classical" meta- to th
- Learmonth, David A.,Bonifácio, Maria Jo?o,Soares-Da-Silva, Patricio
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p. 8070 - 8078
(2007/10/03)
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- IMMOBILIZED N-SUBSTITUTED TRICYCLIC 3-AMINOPYRAZOLES FOR THE IDENTIFICATION OF BIOMOLECULAR TARGETS
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The present invention relates to immobilized N-substituted tricyclic 3-aminopyrazole compounds of Formula 1 as tools for the identification of bimolecular targets in cells of therapeutic significance, profiling the selectivity of compounds, prediction of
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Page/Page column 135
(2008/06/13)
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- TRICYCLIC PYRAZOLE KINASE INHIBITORS
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Compounds of the present invention are useful for inhibiting protein tyrosine kinases. Also disclosed are methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
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Page/Page column 69
(2008/06/13)
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- Method for assaying the sod activity by using a self-oxidizable compound necessary for its implementation, self-oxidizable compounds and preparation thereof
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The method for assaying the SOD (super oxide dismutase) activity in liquid medium is based on the activation of self-oxidization, by SOD activity, of a reactive agent having the general formula (I) wherein either n is 1 or 2, R1 is --OR4 or --NR5 R6 ; R2 is H, --OR4, alkyl (1-6C), --CH2 -- or --CH2 --CH2 --, to form a ring by binding to the phenyl substituent, at meta with respect to R1 ; and R3 is H, alkyl (1-6C) or --OR4 (if R2 is different from --OR4); with R4 being H or alkyl (1-6C); R5 being H, alkyl (1-6C), --CH2 COOH, --C6 H5 COOH or --C6 H5 SO3 H; and R6 is H, alkyl (1-6C) or --CH2 COOH; or n is 1, R1 is --OR4, R2 is --CH2 --O--, in order to form a ring by bonding of O with the phenyl substituent, at meta with respect to R1 ; and R3 is H or --OR4. Application to assaying the SOD activity in a sample, specially a biological sample, particularly by a single measurement and one calibrating curve.
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- Tyrphostins. 2. Heterocyclic and α-Substituted Benzylidenemalonitrile Tyrphostins as Potent Inhibitors of EGF Receptor and ErbB2/neu Tyrosine Kinases
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We have previously described a novel series of low molecular weight protein tyrosine kinase inhibitors which we named tyrphostins.The characteristic active pharmacophore of these compounds was the hydroxy-cis-benzylidenemalonitrile moiety.In this article we describe three novel groups of tyrphostins: (i) one group has the phenolic moiety of the cis-benzylidenemalononitrile replaced either with other substituted benzenes or with heteroaromatic rings, (ii) another is a series of conformationally constrained derivatives of hydroxy-cis-benzylidenemalononitriles in which the malononitrile moiety is fixed relative to the aromatic ring, and (iii) two groups of compounds in which the position trans to the benzenemalononitrile has been substituted by ketones and amides.Among the novel tyrphostins examined we found inhibitors which discriminate between the highly homologous EGF receptor kinase (HER1) and ErbB2/neu kinase (HER2).These findings may lead to selective tyrosine kinase blockers for the treatment of diseases in which ErbB2/neu is involved.
- Gazit, Aviv,Osherov, Nir,Posner, Israel,Yaish, Pnina,Poradosu, Enrique,et al.
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p. 1896 - 1907
(2007/10/02)
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