73889-19-7Relevant academic research and scientific papers
Design and development of novel thiazole-sulfonamide derivatives as a protective agent against diabetic cataract in Wistar rats via inhibition of aldose reductase
Yin, Liang,Zhang, Mingxue,He, Tiangeng
, p. 63 - 70 (2021/10/01)
In recent years, ALR2 (aldose reductase) inhibitors have attracted attention for their effective ability to reduce the progression of diabetes-associated cataracts. Therefore, in the present article, we intended to develop novel thiazole-sulfonamide hybrids as a potent inhibitor of ALR2. These molecules significantly inhibited the ALR2 level in the rat lenses homogenate, where the most potent compound 7b showed activity comparable to sorbinil as standard. In Wistar rats, compound 7b improved the insulin level and body weight of the experimental animal together with a reduction in the glucose output. Compound 7b showed a significant reduction in the expression of ALR2 in rat lenses in western blot analysis.
Claulansine F-donepezil hybrids as anti-alzheimer’s disease agents with cholinergic, free-radical scavenging, and neuroprotective activities
Chen, Xinyi,Li, Chuangjun,Liu, Ke,Ma, Jie,Wang, Weiping,Wang, Xiaoliang,Yang, Jingzhi,Zang, Yingda,Zhang, Dongming
, (2021/05/31)
The multifactorial nature of Alzheimer’s disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A total of 26 Claulansine F-donepezil hybrids were designed and synthesized as multitarget drugs. Among these compounds, six compounds exhibited excellent acetylcholinesterase (AChE) inhibitory activity (half maximal inhibitory concentration (IC50) 1.63-4.62 μM). Moreover, (E)-3-(8-(tert-Butyl)-3,3-dimethyl-3,11-dihydropyrano[3,2-a]carbazol- 5-yl)-N-((1-(2-chlorobenzyl)piperidin-4-yl)methyl)acrylamide (6bd) exhibited better neuroprotective effects against OGD/R (oxygen-glucose deprivation/reoxygenation) than lead compound Claulansine F. Furthermore, 6bd could cross the blood-brain barrier in vitro. More importantly, compared to edaravone, 6bd had stronger free-radical scavenging activity. Molecular docking studies revealed that 6bd could interact with the catalytic active site of AChE. All of these outstanding in vitro results indicate 6bd as a leading structure worthy of further investigation.
Substituted 2-thioxothiazolidin-4-one derivatives showed protective effects against diabetic cataract via inhibition of aldose reductase
Huang, Wanrong,Zhang, Yue,Liang, Xu,Yang, Lichun
, (2020/04/07)
In an effort to develop a new class of potent aldose reductase inhibitors against diabetic cataracts, a series of novel 2-thioxothiazolidine-4-one derivatives was synthesized in excellent yields via a facile synthetic route. These compounds were tested against aldehyde (ALR1) and aldose reductase (ALR2) enzymes, where they showed considerable inhibitory activity. Among the tested derivatives, compound 6e showed selective and excellent inhibition of ALR2 over ALR1. The experimental diabetes was induced by the intraperitoneal administration of streptozotocin in male Wistar rats. Compound 6e showed positive modulation of body weight, blood glucose, and blood insulin levels in diabetic rats. Compound 6e also showed ALR2 inhibition as evidenced by Western blot analysis in lens homogenates of Wistar rats having cataract. The docking study of 6e was also performed inside the active site of ALR2 to enumerate the key contacts for inhibitory activity.
Nitrogen heterocyclic compound, pharmaceutical composition containing nitrogen heterocyclic compound, and preparation method and application of nitrogen heterocyclic compound
-
Paragraph 0493-0497, (2020/08/18)
Disclosed are a nitrogen heterocyclic compound represented by a formula (I), a pharmaceutical composition comprising the same, and a preparation method and use of the nitrogen heterocyclic compound, and in particular, relates to the use of the nitrogen heterocyclic compound for prevention or treatment of diseases or conditions associated with RET activity.
Development of the Convergent, Kilogram-Scale Synthesis of an Antibacterial Clinical Candidate Using Enantioselective Hydrogenation
Benson, Helen,Bones, Karen,Churchill, Gwydion,Ford, Gair,Frodsham, Lianne,Janbon, Sophie,Millington, Fiona,Powell, Lyn,Raw, Steven A.,Reid, Julie,Stark, Andrew,Steven, Alan
, p. 588 - 598 (2020/05/19)
Early chemical development studies into the best way of assembling AZD9742, an antibacterial drug candidate, have involved swapping the order of two reductive aminations. The orthogonally functionalized aminopiperidine partner for these couplings is now enantioselectively synthesized using ruthenium-catalyzed asymmetric hydrogenation. The challenge of controlling defluorination through an appropriate catalyst choice has hitherto prevented this revised sequence from reaching its full potential. However, it is still shown to allow access to the active pharmaceutical ingredient in a stereochemically pure form and has been demonstrated on a multikilogram scale. The reductive aminations in both the original and revised sequences provided different scale-up challenges, and the solutions implemented are described.
Catalytic Transfer Hydrodebenzylation with Low Palladium Loading
Yakukhnov, Sergey A.,Ananikov, Valentine P.
supporting information, p. 4781 - 4789 (2019/09/16)
A highly-efficient catalytic system for hydrodebenzylation reaction is described. The cleavage of O-benzyl and N-benzyl protecting groups was performed using an uncommonly low palladium loading (0.02–0.3 mol%; TON up to 5000) in a relatively short reaction time. The approach was used for a variety of substrates including pharmaceutically important precursors, and gram-scale deprotection reaction was shown. Transfer conditions together with easy-to-make Pd/C catalyst are the key features of this debenzylation scheme. (Figure presented.).
JANUS KINASE 1 SELECTIVE INHIBITOR AND PHARMACEUTICAL USE THEREOF
-
Paragraph 0255-0262, (2018/06/07)
Janus kinase 1 selective inhibitors and pharmaceutical use thereof are provided.
Piperidinyl Ureas Chemically Control Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation
Hammill, Jared T.,Scott, Daniel C.,Min, Jaeki,Connelly, Michele C.,Holbrook, Gloria,Zhu, Fangyi,Matheny, Amy,Yang, Lei,Singh, Bhuvanesh,Schulman, Brenda A.,Guy, R. Kiplin
supporting information, p. 2680 - 2693 (2018/04/23)
We previously discovered and validated a class of piperidinyl ureas that regulate defective in cullin neddylation 1 (DCN1)-dependent neddylation of cullins. Here, we report preliminary structure-activity relationship studies aimed at advancing our high-throughput screen hit into a tractable tool compound for dissecting the effects of acute DCN1-UBE2M inhibition on the NEDD8/cullin pathway. Structure-enabled optimization led to a 100-fold increase in biochemical potency and modestly increased solubility and permeability as compared to our initial hit. The optimized compounds inhibit the DCN1-UBE2M protein-protein interaction in our TR-FRET binding assay and inhibit cullin neddylation in our pulse-chase NEDD8 transfer assay. The optimized compounds bind to DCN1 and selectively reduce steady-state levels of neddylated CUL1 and CUL3 in a squamous cell carcinoma cell line. Ultimately, we anticipate that these studies will identify early lead compounds for clinical development for the treatment of lung squamous cell carcinomas and other cancers.
Comprehensive Synthesis of Amino Acid-Derived Thiazole Peptidomimetic Analogues to Understand the Enigmatic Drug/Substrate-Binding Site of P-Glycoprotein
Patel, Bhargav A.,Abel, Biebele,Barbuti, Anna Maria,Velagapudi, Uday Kiran,Chen, Zhe-Sheng,Ambudkar, Suresh V.,Talele, Tanaji T.
, p. 834 - 864 (2018/02/17)
A novel set of 64 analogues based on our lead compound 1 was designed and synthesized with an initial objective of understanding the structural requirements of ligands binding to a highly perplexing substrate-binding site of P-glycoprotein (P-gp) and their effect on modulating the ATPase function of the efflux pump. Compound 1, a stimulator of P-gp ATPase activity, was transformed to ATPase inhibitory compounds 39, 53, and 109. The ATPase inhibition by these compounds was predominantly contributed by the presence of a cyclohexyl group in lieu of the 2-aminobenzophenone moiety of 1. The 4,4-difluorocyclohexyl analogues, 53 and 109, inhibited the photolabeling by [125I]-IAAP, with IC50 values of 0.1 and 0.76 μM, respectively. Selected compounds were shown to reverse paclitaxel resistance in HEK293 cells overexpressing P-gp and were selective toward P-gp over CYP3A4. Induced-fit docking highlighted a plausible binding pattern of inhibitory compounds in the putative-binding pocket of P-gp. The current study underscores the stringent requirement by P-gp to bind to chemically similar molecules.
Design and development of a novel chalcone derivative as an anticholinesterase inhibitor for possible treatment of dementia
Zhao, Fu-Chun,Wu, Yan,Song, Xiao-Jie
, p. 3311 - 3317 (2017/07/17)
Background: Cognitive decline (e.g., memory loss), which mainly occurs in the elderly, is termed dementia. In the present study, we intended to explore the cholinesterase inhibitory activity of some novel synthesized chalcones, together with their effect on β-amyloid anti-aggregation. Material/Methods: A novel class of chalcone derivatives have been synthesized and characterized by FT-IR,1H-NMR,13C-NMR, and mass and elemental analysis. These derivatives were later used for the determination of acetylcholinesterase (AChE) inhibitory and β-amyloid anti-aggregation activity. Results: The results of the study showed that among the developed compounds, 8g inhibits AChE more prominently than BuChE, as suggested by a selectivity index (SI) of 2.88. Furthermore, the most potent compound, 8g, showed considerable action in inhibition of β-secretase and Aβ aggregation, but not as prominent as that of curcumin as a standard. Conclusions: In conclusion, our study revealed a novel class of chalcone derivatives as a selective inhibitor of AChE with considerably action against β-secretase and Aβ aggregation. Our results may be useful in developing AD drug therapy and warrant further investigation to generate more advanced analogues.
