- Discovery of Novel Tacrine-Pyrimidone Hybrids as Potent Dual AChE/GSK-3 Inhibitors for the Treatment of Alzheimer's Disease
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Based on a multitarget strategy, a series of novel tacrine-pyrimidone hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation results demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and glycogen synthase kinase 3 (GSK-3). The optimal compound 27g possessed excellent dual AChE/GSK-3 inhibition both in terms of potency and equilibrium (AChE: IC50 = 51.1 nM; GSK-3β: IC50 = 89.3 nM) and displayed significant amelioration on cognitive deficits in scopolamine-induced amnesia mice and efficient reduction against phosphorylation of tau protein on Ser-199 and Ser-396 sites in glyceraldehyde (GA)-stimulated differentiated SH-SY5Y cells. Furthermore, compound 27g exhibited eligible pharmacokinetic properties, good kinase selectivity, and moderate neuroprotection against GA-induced reduction in cell viability and neurite damage in SH-SY5Y-derived neurons. The multifunctional profiles of compound 27g suggest that it deserves further investigation as a promising lead for the prospective treatment of AD.
- Yao, Hong,Uras, Giuseppe,Zhang, Pengfei,Xu, Shengtao,Yin, Ying,Liu, Jie,Qin, Shuai,Li, Xinuo,Allen, Stephanie,Bai, Renren,Gong, Qi,Zhang, Haiyan,Zhu, Zheying,Xu, Jinyi
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p. 7483 - 7506
(2021/06/28)
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- Br?nsted Acid-Catalyzed Asymmetric Ring-Closing Alkylation of Inert N-substituted Pyrroles with α, β-Unsaturated Ketones
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A Chiral Br?nsted acid catalyzed asymmetric intramolecular ring-closing alkylation of inert pyrroles with α, β-unsaturated ketones has been developed. This approach gave a wide range of 4-phenyl-4,5-dihydro-6H-benzo[f]pyrrolo[1,2-a]azepin-6-ones in high yields with good enantioselectivities under mild reaction conditions. (Figure presented.).
- Wei, Zhao,Zhang, Jinlong,Yang, Huameng,Jiang, Gaoxi
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supporting information
p. 3694 - 3697
(2019/07/12)
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- Molecular Hybridization-Inspired Optimization of Diarylbenzopyrimidines as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors with Improved Activity against K103N and E138K Mutants and Pharmacokinetic Profiles
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Molecular hybridization is a powerful strategy in drug discovery. A series of novel diarylbenzopyrimidine (DABP) analogues were developed by the hybridization of FDA-approved drugs etravirine (ETR) and efavirenz (EFV) as potential HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). Substituent modifications resulted in the identification of new DABPs with the combination of the strengths of the two drugs, especially compound 12d, which showed promising activity toward the EFV-resistant K103N mutant. 12d also had a favorable pharmacokinetic (PK) profile with liver microsome clearances of 14.4 μL/min/mg (human) and 33.2 μL/min/mg (rat) and an oral bioavailability of 15.5% in rat. However, its activity against the E138K mutant was still unsatisfactory; E138K is the most prevalent NNRTI resistance-associated mutant in ETR treatment. Further optimizations resulted in a highly potent compound (12z) with no substituents on the phenyl ring and a 2-methyl-6-nitro substitution pattern on the 4-cyanovinyl-2,6-disubstitued phenyl motif. The antiviral activity of this compound was much higher than those of ETR and EFV against the WT, E138K, and K103N variants (EC50 = 3.4, 4.3, and 3.6 nM, respectively), and the cytotoxicity was decreased while the selectivity index (SI) was increased. In particular, this compound exhibited acceptable intrinsic liver microsome stability (human, 34.5 μL/min/mg; rat, 33.2 μL/min/mg) and maintained the good PK profile of its parent compound EFV and showed an oral bioavailability of 16.5% in rat. Molecular docking and structure-activity relationship (SAR) analysis provided further insights into the binding of the DABPs with HIV-1 reverse transcriptase and provided a deeper understanding of the key structural features responsible for their interactions.
- Han, Sheng,Sang, Yali,Wu, Yan,Tao, Yuan,Pannecouque, Christophe,De Clercq, Erik,Zhuang, Chunlin,Chen, Fen-Er
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- 19F magnetic resonance probes for live-cell detection of peroxynitrite using an oxidative decarbonylation reaction
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We report a newly discovered oxidative decarbonylation reaction of isatins that is selectively mediated by peroxynitrite (ONOO-) to provide anthranilic acid derivatives. We have harnessed this rapid and selective transformation to develop two reaction-based probes, 5-fluoroisatin and 6-fluoroisatin, for the low-background readout of ONOO- using 19F magnetic resonance spectroscopy. 5-fluoroisatin was used to non-invasively detect ONOO- formation in living lung epithelial cells stimulated with interferon-γ (IFN-γ). This journal is
- Bruemmer, Kevin J.,Merrikhihaghi, Sara,Lollar, Christina T.,Morris, Siti Nur Sarah,Bauer, Johannes H.,Lippert, Alexander R.
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supporting information
p. 12311 - 12314
(2015/02/19)
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- Synthesis of novel quinazolinone derivatives with methyl (E)-2-(3-methoxy)acrylate moiety
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A new series of quinazolinone derivatives with methyl (E)-2-(3-methoxy) acrylate moiety have been designed and synthesized. All target compounds had been identified by 1H NMR spectrum, IR spectrum and HR-MS (high resolution mass spectrum). Three target compounds (10a, 10e, 10h) were chosen to preliminarily test the antibacterial activities, the results showed that all three target compounds exhibited antibacterial activities against three bacterial strains (Proteobacteria, Salmonella, Colibacillus).
- Dong, Kui-Kui,Zhou, Hua-Hong,Guo, A-Rong,Chen, Tian,Wang, Yu-Liang
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p. 1039 - 1042
(2013/05/08)
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- Catalysis and mechanistic studies of ruthenium and osmium on synthesis of anthranilic acids
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Ruthenium, osmium and ruthenium + osmium catalyzed synthetic methodology was developed for the synthesis of anthranilic acids from indoles in good to excellent yields using bromamine-B in alkaline acetonitrile-water (1:1) at 313 K. Detailed catalysis studies of ruthenium, osmium and the mixture of both were carried out for the synthetic reactions. The positive synergistic catalytic activity of Ru(III) + Os(VIII) was observed to a large extent with the activity greater than the sum of their separate catalytic activities. Detailed kinetic and mechanistic investigations for each catalyzed reactions were carried out. The kinetic pattern and mechanistic picture of each catalyzed reaction were found to be different for each catalyst and to obey the underlying rate laws: rate = k[BAB]t[Indole][Ru(III)]x[OH-] y rate = k[BAB]t[Indole][Os(VIII)][OH-] y rate = k[BAB]t[Indole]o[Ru(III) + Os(VIII)][OH-]y where, x, y Os(VIII) > Ru(III). This trend may be attributed to the different d-electronic configuration of the catalysts. The proposed mechanisms and the rigorous kinetic models derived give results that fit well with the experimental data in each catalyzed reaction. Copyright
- Karthikeyan,Jagadeesh, Rajenahally V.,Sree Sandhya,Puttaswamy,Nithya,Kumar, S. Senthil,Bhagat
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experimental part
p. 34 - 46
(2011/09/16)
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- Bromamine-B/PdCl2 is an efficient system for the synthesis of anthranilic acids from indoles and indigos
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A convenient method has been developed for the conversion of indoles and indigos into anthranilic acids in good to excellent yields using a bromamine-B/PdCl2 system. The general process utilizes our efficient method for the oxidation of indoles and indigos in alkaline (pH 12) acetonitrile/water (1:1) at 60°C. Copyright Taylor & Francis Group, LLC.
- Kumar, C. Vinod,Shivananda,Raju, C. Nagu,Jagadeesh
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experimental part
p. 3480 - 3487
(2011/02/22)
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- Synthesis of new 1,2,3-triazolo[1,5-a]quinazolinones
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(Chemical Equation Presented) Synthesis of novel 3-substituted-1,2,3- triazolo[1,5-a]quinazolinones in high yields was performed via anionic hetero-domino reaction of appropriate substituted 2-azidobenzoates prepared from isatines and acetonitriles activated by 1,3-thiazole, 1,3-benzothiazole, 1,3,4-oxadiazole, and 1,2,4-oxadiazole rings. It was shown that acetonitriles exhibited high reactivity and were convenient methylenic compounds for such reactions providing rapid structural variation.
- Pokhodylo, Nazariy T.,Matiychuk, Vasyl S.
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scheme or table
p. 415 - 420
(2010/06/16)
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- TUMOR NECROSIS FACTOR ALPHA INHIBITORS AND THEIR USE IN THE TREATMENT OF HUMAN DISEASES
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treatment of a variety of disorders, including the treatment of pathological conditions associated with tumor necrosis factor alpha. The inhibitors of tumor necrosis factor alpha have the following structures: including stereoisomers, pharmaceutically acceptable salts, and solvates thereof, wherein substituents are as defined herein. Compositions containing an inhibitor of tumor necrosis factor alpha in combination with a pharmaceutically acceptable carrier are also provided, as well as methods for use of the same.
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- PYRIMIDINE DERIVATIVES AS MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS
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The present invention relates to compounds of Formula (I) as modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.
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Page/Page column 313
(2008/06/13)
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- INHIBITORS OF MACROPHAGE MIGRATION INHIBITORY FACTOR AND METHODS FOR IDENTIFYING THE SAME
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Inhibitors of MIF are provided which have utility in the treatment of a variety of disorders, including the treatment of pathological conditions associated with MIF activity. The inhibitors of MIF have the following structures (Ia), (Ib) including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein n, R1, R2, R3, R4, X, and Z are as defined herein. Compositions containing an inhibitor of MIF in combination with a pharmaceutically acceptable carrier are also provided, as well as methods for use of the same.
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- Condensed pyrazole derivatives, process for producing the same and use thereof
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Novel pharmaceutical compositions for inhibiting Th2-selective immune response and pharmaceutical compositions for inhibiting cyclooxygenase comprising condensed pyrazole derivatives represented by the general formula (I): or salts thereof.
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- Process for the preparation of 5-fluoroanthranilic acid
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The present invention relates to a process for the preparation of 5-fluoroanthranilic acid, which comprises reacting 5-fluoro-2-bromotoluene in the presence of a catalyst and of an acidic solvent, with oxygen or an oxygen-containing gas at from 80° to 220° C., separating off the 5-fluoro-2-bromobenzoic acid formed and reacting it with ammonia at from 70° to 180° C.
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- Process for the preparation of 5-fluoroanthranilic alkyl esters and/or 5-fluoroanthranilic acid
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The present invention relates to a process for the preparation of 5-fluoroanthranilic alkyl esters and/or 5-fluoroanthranilic acid, which comprises dissolving a 3-fluorobenzoic alkyl ester in sulfuric acid and reacting the solution with a nitrating acid at from -10° to 30° C., then adding water, separating off the nitrated reaction product and reacting it with hydrogen at from 50° to 120° C. under elevated pressure in the presence of a catalyst comprising a metal of the platinum group and sulfur, and, if desired, removing 5-fluoroanthranilic alkyl esters by distillation and hydrolyzing them to give 5-fluoroanthranilic acid.
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- Amino-benzoic acids and derivatives, and methods of use
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The present invention relates to compounds, compositions and methods for inhibiting nonenzymatic cross-linking (protein aging). Accordingly, a composition is disclosed which comprises an agent capable of inhibiting the formation of advanced glycosylation endproducts of target proteins by reacting with a carbonyl moiety of the early glycosylation product of such target proteins formed by their initial glycosylation. The method comprises contacting the target protein with the composition. Both industrial and therapeutic applications for the invention are envisioned, as food spoilage and animal protein aging can be treated.
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