446-08-2Relevant articles and documents
Discovery of Novel Tacrine-Pyrimidone Hybrids as Potent Dual AChE/GSK-3 Inhibitors for the Treatment of Alzheimer's Disease
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
, p. 7483 - 7506 (2021/06/28)
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.
Molecular Hybridization-Inspired Optimization of Diarylbenzopyrimidines as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors with Improved Activity against K103N and E138K Mutants and Pharmacokinetic Profiles
Han, Sheng,Sang, Yali,Wu, Yan,Tao, Yuan,Pannecouque, Christophe,De Clercq, Erik,Zhuang, Chunlin,Chen, Fen-Er
, (2019/11/11)
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.
Br?nsted Acid-Catalyzed Asymmetric Ring-Closing Alkylation of Inert N-substituted Pyrroles with α, β-Unsaturated Ketones
Wei, Zhao,Zhang, Jinlong,Yang, Huameng,Jiang, Gaoxi
supporting information, p. 3694 - 3697 (2019/07/12)
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.).
19F magnetic resonance probes for live-cell detection of peroxynitrite using an oxidative decarbonylation reaction
Bruemmer, Kevin J.,Merrikhihaghi, Sara,Lollar, Christina T.,Morris, Siti Nur Sarah,Bauer, Johannes H.,Lippert, Alexander R.
supporting information, p. 12311 - 12314 (2015/02/19)
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
Synthesis of novel quinazolinone derivatives with methyl (E)-2-(3-methoxy)acrylate moiety
Dong, Kui-Kui,Zhou, Hua-Hong,Guo, A-Rong,Chen, Tian,Wang, Yu-Liang
, p. 1039 - 1042 (2013/05/08)
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).
Catalysis and mechanistic studies of ruthenium and osmium on synthesis of anthranilic acids
Karthikeyan,Jagadeesh, Rajenahally V.,Sree Sandhya,Puttaswamy,Nithya,Kumar, S. Senthil,Bhagat
experimental part, p. 34 - 46 (2011/09/16)
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
Bromamine-B/PdCl2 is an efficient system for the synthesis of anthranilic acids from indoles and indigos
Kumar, C. Vinod,Shivananda,Raju, C. Nagu,Jagadeesh
experimental part, p. 3480 - 3487 (2011/02/22)
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.
Synthesis of new 1,2,3-triazolo[1,5-a]quinazolinones
Pokhodylo, Nazariy T.,Matiychuk, Vasyl S.
scheme or table, p. 415 - 420 (2010/06/16)
(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.
TUMOR NECROSIS FACTOR ALPHA INHIBITORS AND THEIR USE IN THE TREATMENT OF HUMAN DISEASES
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Page/Page column 43, (2008/12/06)
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.
PYRIMIDINE DERIVATIVES AS MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS
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Page/Page column 313, (2008/06/13)
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.
