635-21-2Relevant academic research and scientific papers
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.
Expedient discovery for novel antifungal leads: 1,3,4-Oxadiazole derivatives bearing a quinazolin-4(3H)-one fragment
Chai, Jianqi,Chen, Min,Jin, Fei,Kong, Xiangyi,Wang, Xiaobin,Xue, Wei,Yang, Chunlong
, (2021/08/03)
Developing novel fungicide candidates are intensively promoted by the rapid emergences of resistant fungi that outbreak on agricultural production. Aiming to discovery novel antifungal leads, a series of 1,3,4-oxadiazole derivatives bearing a quinazolin-4(3H)-one fragment were constructed for evaluating their inhibition effects against phytopathogenic fungi in vitro and in vivo. Systematically structural optimizations generated the bioactive molecule I32 that was identified as a promising inhibitor against Rhizoctonia solani with the in vivo preventative effect of 58.63% at 200 μg/mL. The observations that were captured by scanning electron microscopy and transmission electron microscopy demonstrated that the bioactive molecule I32 could induce the sprawling growth of hyphae, the local shrinkage and rupture on hyphal surfaces, the extreme swelling of vacuoles, the striking distortions on cell walls, and the reduction of mitochondria numbers. The above results provided an indispensable complement for the discovery of antifungal lead bearing a quinazolin-4(3H)-one and 1,3,4-oxadiazole fragment.
Monitoring intracellular pH fluctuation with an excited-state intramolecular proton transfer-based ratiometric fluorescent sensor
Feng, Bin,Zhu, Yingli,Wu, Jiaxin,Huang, Xueyan,Song, Rong,Huang, Liu,Feng, Xueping,Zeng, Wenbin
, p. 3057 - 3060 (2021/04/12)
Intracellular pH is a key parameter related to various biological and pathological processes. In this study, a ratiometric pH fluorescent sensor ABTT was developed harnessing the amino-type excited-state intramolecular proton transfer (ESIPT) process. Relying on whether the ESIPT proceeds normally or not, ABTT exhibited the yellow fluorescence in acidic media, or cyan fluorescence in basic condition. According to the variation, ABTT behaved as a promising sensor which possessed fast and reversible response to pH change without interference from the biological substances, and exported a steady ratiometric signal (I478/I546). Moreover, due to the ESIPT effect, large Stokes shift and high quantum yield were also exhibited in ABTT. Furthermore, ABTT was applied for monitoring the pH changes in living cells and visualizing the pH fluctuations under oxidative stress successfully. These results elucidated great potential of ABTT in understanding pH-dependent physiological and pathological processes.
Preparation method of 5-chloro-2-aminobenzoic acid intermediate
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Paragraph 0017-0020, (2021/08/11)
The invention discloses a preparation method of 5-chloro-2-aminobenzoic acid, and belongs to the technical field of organic synthesis, the preparation method specifically comprises the following steps: dissolving 2, 5-dichlorotoluene in a solvent, adding an oxidant while stirring, heating to 50-80 DEG C, carrying out heat preservation reaction for 3-6 hours, recovering the organic solvent after the reaction is finished, adding water, filtering while hot, and adjusting the pH value of the filtrate to 2 by using hydrochloric acid, obtaining 2, 5-dichlorobenzoic acid through cooling, crystallization and filtering, adding 2, 5-dichlorobenzoic acid into an organic solvent to be dissolved, addign a metal catalyst, alkali and an ammonia source, heating the mixture to 70-150 DEG C and then performing a heat preservation reaction for 8-15 h, performing reduced pressure distillation after the reaction is finished, and obtaining 5-chloro-2-aminobenzoic acid. A new path for synthesizing 5-chloro-2-aminobenzoic acid is designed, the preparation method is simple, easy to operate, low in cost and environmentally friendly, and N, N-dimethylglycine is added in the ammoniation reaction process, so that the temperature of the ammoniation reaction can be reduced, the reaction time can be shortened, and the reaction yield can be increased.
Selenium-catalyzed intramolecular atom- And redox-economical transformation ofo-nitrotoluenes into anthranilic acids
Jiang, Xuefeng,Li, Yiming,Lin, Zhenyang,Wang, Yuhong,Yang, Tilong
supporting information, p. 2986 - 2991 (2021/05/05)
Anthranilic acids (AAs) are significant basic chemicals used in pharmaceuticals, agrochemicals, dyes, fragrances,etc. Superfluous steps are always involved in obtaining AAs. Herein, we demonstrate a straightforward strategy to transform abundanto-nitrotoluenes into biologically and pharmaceutically significant AAs without any extra reductants, oxidants and protecting groups. Various sensitive groups, such as halogens, sulfide, aldehyde, pyridines, quinolines,etc., can be tolerated in this transformation. A hundred-gram-scale operation is realized efficiently with almost quantitative selenium recycling. Further mechanistic studies and DFT calculations disclosed the proposed atom-exchange processes and the key roles of the selenium species.
Anthranilic acid and derivatives thereof as well as synthesis method and application thereof
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Paragraph 0080-0082, (2021/09/15)
In the reaction solvent, o-methyl (hetero) aryl nitro compound is taken as a reaction raw material and is used for water. The anthranilic acid and its derivatives are synthesized by the action of a catalyst, a base and an additive. The synthetic method has the advantages of cheap and easily available raw materials, simple reaction operation, high yield and excellent functional group tolerance, and provides a simple and efficient method for synthesizing o-aminobenzoic acid which is widely used in the aspects of dyes, medicines, pesticides, spices and the like. The invention further discloses the anthranilic acid and derivatives and application thereof, and has a wide application prospect.
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.).
Functionalization of Quinazolin-4-ones Part 3: Synthesis, Structures Elucidation, DNA-PK, PI3K, and Cytotoxicity of Novel 8-Aryl-2-morpholino-quinazolin-4-ones
Heppell, Jacob T.,Islam, Md. Amirul,McAlpine, Shelli R.,Al-Rawi, Jasim M. A.
, p. 124 - 141 (2018/12/11)
A series of novel 8-aryl-2-morpholino quinazolines (11a–n, 12a–d, 14a–f, and 15) were synthesized from the precursor 2-thioxo quinazolin-4-ones 8. The 8-aryl-2-morpholino quinazolines compounds were assayed for DNA-PK and PI3K. All compounds showed low DNA-PK % inhibition activity at 10?μM compound concertation, and the most active was 8-(dibenzo[b,d]thiophen-4-yl) 12d with 38% inhibition. Similar pattern of PI3K α, β, γ, and δ isoforms inhibition activity at 10?μM were observed. The most active isoform was PI3K δ of 41% inhibition for 8-(dibenzo[b,d]furan-4-yl) compound 11. Most compounds were less active than expected in spite of the strong structural resemblance to known inhibitors (NU7441, 3, 4, and 6). Loss of activity could be attributed to the tautomerization to the aromatic enol (4-OH), which could specify that the important functional group for the activity is the 4-carbonyl (C=O) group. Alternatively, the aromatization of the pyrimidine heterocyclic ring could alter the conformation, and thus binding site, of the 2-morpholine ring, which could reduce the compound-receptor hydrogen bonding to the morpholine 4-oxygen. Selected compounds displayed appreciable cytotoxicity with 6-chloro-8-(dibenzo[b,d]thiophen-4-yl)-2-morpholinoquinazolin-4(1H)-one 11j exhibiting the greatest activity with an IC50 of 9.95?μM. Therefore, the mechanism of the cytotoxicity of compound 11j were not through DNA-PK or PI3K inhibition activity.
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.
Structure and biocatalytic scope of thermophilic flavin-dependent halogenase and flavin reductase enzymes
Menon, Binuraj R. K.,Latham, Jonathan,Dunstan, Mark S.,Brandenburger, Eileen,Klemstein, Ulrike,Leys, David,Karthikeyan, Chinnan,Greaney, Michael F.,Shepherd, Sarah A.,Micklefield, Jason
supporting information, p. 9354 - 9361 (2016/10/13)
Flavin-dependent halogenase (Fl-Hal) enzymes have been shown to halogenate a range of synthetic as well as natural aromatic compounds. The exquisite regioselectively of Fl-Hal enzymes can provide halogenated building blocks which are inaccessible using standard halogenation chemistries. Consequently, Fl-Hal are potentially useful biocatalysts for the chemoenzymatic synthesis of pharmaceuticals and other valuable products, which are derived from haloaromatic precursors. However, the application of Fl-Hal enzymes, in vitro, has been hampered by their poor catalytic activity and lack of stability. To overcome these issues, we identified a thermophilic tryptophan halogenase (Th-Hal), which has significantly improved catalytic activity and stability, compared with other Fl-Hal characterised to date. When used in combination with a thermostable flavin reductase, Th-Hal can efficiently halogenate a number of aromatic substrates. X-ray crystal structures of Th-Hal, and the reductase partner (Th-Fre), provide insights into the factors that contribute to enzyme stability, which could guide the discovery and engineering of more robust and productive halogenase biocatalysts.
