76903-88-3Relevant academic research and scientific papers
Benzoyl-containing rupestonic acid methyl ester derivative as well as preparation method and application thereof
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Paragraph 0032; 0066; 0070, (2021/06/22)
The invention relates to a benzoyl-containing rupestonic acid methyl ester derivative as well as a preparation method and application thereof. Rupestonic acid and dimethyl sulfate react to obtain rupestonic acid methyl ester, 2-hydroxyl rupestonic acid methyl ester is prepared under oxidation of camphor sulfonyl acridine, and then the 2-hydroxyl rupestonic acid methyl ester reacts with different substituted benzoyl chloride under the catalysis of DMAP to obtain the 1d-15d benzoyl-containing rupestonic acid methyl ester derivative. The method has the advantages of mild reaction conditions and simple experimental steps. The obtained benzoyl-containing rupestonic acid methyl ester derivative 1d-15d is subjected to an anti-H3N2 influenza A virus activity test in 1d-15d. Experimental results show that the compounds 1d, 2d, 4d, 5d, 7d, 8d, 12d, 13d and 15d can be applied to preparation of drugs for resisting influenza A H3N2 virus.
One-step Conversion of Amides and Esters to Acid Chlorides with PCl3
Li, Fangshao,Wu, Xiaofang,Guo, Fengzhe,Tang, Zi-Long,Xiao, Jing
supporting information, p. 4314 - 4317 (2021/07/16)
A general and efficient iodine-promoted chlorination of amides and esters with phosphorus trichloride is described. For the first time. Various inactivated amides including secondary and tertiary amides were directly converted to the corresponding acid chlorides in one-step. The substrate scope of methyl esters including aromatic and aliphatic esters was also explored under this system. This method is simple, scalable and wide in scope, which provides an approach to preparation of these acid chlorides.
Idnhibition of antibacterial resistance by 3',4'-difluoroquercetin and its derivative
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Paragraph 0097-0099, (2020/09/16)
The present invention relates to 3andprime;,4andprime;-difluoroquercetin having antibacterial activity on multiple drug resistant bacteria and a novel derivative thereof. A quercetin derivative compound of the present invention exhibits a significant antibacterial activity on Gram-positive multiple drug resistant bacteria, exhibits strong antibacterial activity only on Gram-negative multiple drug resistant bacteria, and a significant synergistic effect occurs when an antibiotic which does not have antibacterial activity or has low antibacterial activity and the compound of the present invention are mixed and treated in Gram-negative multiple drug resistant bacteria, thereby being able to exhibit an excellent antibacterial effect on Gram-positive multiple drug resistant bacteria, Gram-negative multiple drug resistant bacteria, and antibiotic-resistant bacteria thereof.COPYRIGHT KIPO 2020
Discovery of methoxy-naphthyl linked N-(1-benzylpiperidine) benzamide as a blood-brain permeable dual inhibitor of acetylcholinesterase and butyrylcholinesterase
Abdullaha, Mohd,Bharate, Sandip B.,Nuthakki, Vijay K.
, (2020/09/18)
The cholinesterase enzymes play a vital role in maintaining balanced levels of the neurotransmitter acetylcholine in the central nervous system. However, the overexpression of these enzymes results in hampered neurotransmission. Both the major forms of cholinesterase enzymes viz. acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) play a crucial role in blocking neurotransmission; therefore, in recent years, a strategy of dual cholinesterase inhibition is being explored. Herein, we developed an energy-optimized e-pharmacophore hypothesis AHHPRR from AChE-donepezil complex and screened a set of 15 scaffolds that were designed imaginarily. The ligand with N-(1-benzylpyridinium) benzamide framework has shown the highest fitness and volume score, which was chosen for synthesis and validation. A series of pyridinium benzamides were synthesized and screened for cholinesterase inhibition that led to the identification of 7b, a naphthalene containing N-(1-benzylpiperidine) benzamide as a potent dual AChE and BChE inhibitor with IC50 values of 0.176, and 0.47 μM, respectively. The kinetic study indicated that 7b inhibits AChE in a non-competitive manner with Ki value of 0.21 μM, and BChE in a mixed-fashion with Ki of 0.15 μM. The observed mode of inhibition was corroborated with molecular docking studies. The MD simulation studies pointed out that both AChE and BChE undergo low conformational changes in complex with 7b. The benzamide 7b displayed high BBB permeability in PAMPA assay, which indicates its potential for further exploration in preclinical studies for Alzheimer's disease.
Identification of Phenylpyrazolone Dimers as a New Class of Anti-Trypanosoma cruzi Agents
Sijm, Maarten,Siciliano de Araújo, Julianna,Ramos Llorca, Alba,Orrling, Kristina,Stiny, Lydia,Matheeussen, An,Maes, Louis,de Esch, Iwan J. P.,de Nazaré Correia Soeiro, Maria,Sterk, Geert Jan,Leurs, Rob
supporting information, p. 1662 - 1668 (2019/08/30)
Chagas disease is becoming a worldwide problem; it is currently estimated that over six million people are infected. The two drugs in current use, benznidazole and nifurtimox, require long treatment regimens, show limited efficacy in the chronic phase of infection, and are known to cause adverse effects. Phenotypic screening of an in-house library led to the identification of 2,2′-methylenebis(5-(4-bromophenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one), a phenyldihydropyrazolone dimer, which shows an in vitro pIC50 value of 5.4 against Trypanosoma cruzi. Initial optimization was done by varying substituents of the phenyl ring, after which attempts were made to replace the phenyl ring. Finally, the linker between the dimer units was varied, ultimately leading to 2,2′-methylenebis(5-(3-bromo-4-methoxyphenyl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (NPD-0228) as the most potent analogue. NPD-0228 has an in vitro pIC50 value of 6.4 against intracellular amastigotes of T. cruzi and no apparent toxicity against the human MRC-5 cell line and murine cardiac cells.
Structural Basis for Achieving GSK-3β Inhibition with High Potency, Selectivity, and Brain Exposure for Positron Emission Tomography Imaging and Drug Discovery
Bernard-Gauthier, Vadim,Mossine, Andrew V.,Knight, Ashley,Patnaik, Debasis,Zhao, Wen-Ning,Cheng, Chialin,Krishnan, Hema S.,Xuan, Lucius L.,Chindavong, Peter S.,Reis, Surya A.,Chen, Jinshan Michael,Shao, Xia,Stauff, Jenelle,Arteaga, Janna,Sherman, Phillip,Salem, Nicolas,Bonsall, David,Amaral, Brenda,Varlow, Cassis,Wells, Lisa,Martarello, Laurent,Patel, Shil,Liang, Steven H.,Kurumbail, Ravi G.,Haggarty, Stephen J.,Scott, Peter J. H.,Vasdev, Neil
supporting information, p. 9600 - 9617 (2019/10/28)
Using structure-guided design, several cell based assays, and microdosed positron emission tomography (PET) imaging, we identified a series of highly potent, selective, and brain-penetrant oxazole-4-carboxamide-based inhibitors of glycogen synthase kinase-3 (GSK-3). An isotopologue of our first-generation lead, [3H]PF-367, demonstrates selective and specific target engagement in vitro, irrespective of the activation state. We discovered substantial ubiquitous GSK-3-specific radioligand binding in Tg2576 Alzheimer's disease (AD), suggesting application for these compounds in AD diagnosis and identified [11C]OCM-44 as our lead GSK-3 radiotracer, with optimized brain uptake by PET imaging in nonhuman primates. GSK-3β-isozyme selectivity was assessed to reveal OCM-51, the most potent (IC50 = 0.030 nM) and selective (>10-fold GSK-3β/GSK-3α) GSK-3β inhibitor known to date. Inhibition of CRMP2T514 and tau phosphorylation, as well as favorable therapeutic window against WNT/β-catenin signaling activation, was observed in cells.
Design, synthesis, structure-activity relationships study and X-ray crystallography of 3-substituted-indolin-2-one-5-carboxamide derivatives as PAK4 inhibitors
Guo, Jing,Zhao, Fan,Yin, Wenbo,Zhu, Mingyue,Hao, Chenzhou,Pang, Yu,Wu, Tianxiao,Wang, Jian,Zhao, Dongmei,Li, Haitao,Cheng, Maosheng
, p. 197 - 209 (2018/06/12)
We have previously described the identification of indolin-2-one-5-carboxamides as potent PAK4 inhibitors. This study expands the structure-activity relationships on our original series by presenting several modifications in the lead compounds, 2 and 3. A series of novel derivatives was designed, synthesized, and evaluated in biochemical and cellular assay. Most of this series displayed nanomolar biochemical activity and potent antiproliferative activity against A549 and HCT116 cells. The representative compound 10a exhibited excellent enzyme inhibition (PAK4 IC50 = 25 nM) and cellular potency (A549 IC50 = 0.58 μM, HCT116 IC50 = 0.095 μM). An X-ray structure of compound 10a bound to PAK4 was obtained. Crystallographic analysis confirmed predictions from molecular modeling and helped refine SAR results. In addition, Compound 10a displayed focused multi-targeted kinase inhibition, good calculated drug-likeness properties. Further profiling of compound 10a revealed it showed weak inhibitory activity against various isoforms of human cytochrome P450.
Synthesis and biological evaluation of fluorinated N-benzoyl and N-phenylacetoyl derivatives of 3-(4-aminophenyl)-coumarin-7-O-sulfamate as steroid sulfatase inhibitors
Da?ko, Mateusz,Przyby?owska, Maja,Rachon, Janusz,Mas?yk, Maciej,Kubiński, Konrad,Misiak, Majus,Sk?adanowski, Andrzej,Demkowicz, Sebastian
, p. 79 - 87 (2017/02/05)
In the present work, we report convenient methods for the synthesis of 3-(4-aminophenyl)-coumarin-7-O-sulfamate derivatives N-acylated with fluorinated analogues of benzoic or phenylacetic acid as steroid sulfatase (STS) inhibitors. The design of these potential STS inhibitors was supported by molecular modeling techniques. Additionally, computational docking methods were used to determine the binding modes of the synthesized inhibitors and to identify potential interactions between inhibitors and amino acid residues located in the active site of STS. The inhibitory effects of the synthesized compounds were tested on STS isolated from human placenta and against estrogen receptor-(ER)-positive MCF-7 and T47D cells, as well as ER-negative MDA-MB-231 and SkBr3 cancer cell lines. In the course of our investigation, compounds 6c and 6j demonstrated the highest inhibitory effect in enzymatic STS assays, both with IC50values of 0.18?μM (the IC50value of coumarin-7-O-sulfamate is 1.38?μM, used as a reference). Compound 6j exhibited the highest potency against the MCF-7 and T47D cell lines (15.9?μM and 8.7?μM, respectively). The GI50values of tamoxifen (used as a reference) were 6.8; 10.6; 15.1; 12.5?μM against MCF-7, T47D, MDA-MB-231 and SkBr3 cancer cell lines, respectively. Despite the slightly lower activity of compounds 1 and 2 (both in enzymatic and cell-based experiments) compared to 6g and 6j, analogues 1 and 2 proved to selectively inhibit the growth of ER- and PR-positive cell lines.
Synthesis and biological evaluation of N-acylated tyramine sulfamates containing C–F bonds as steroid sulfatase inhibitors
Da?ko, Mateusz,Rachon, Janusz,Mas?yk, Maciej,Kubiński, Konrad,Demkowicz, Sebastian
, p. 156 - 161 (2017/06/19)
Steroid sulfatase (STS) is responsible for the hydrolysis of biologically inactive sulfated steroids into their active un-sulfated forms and promotes the growth of various hormone-dependent cancers (e.g., breast cancer). Therefore, the STS enzyme is a promising therapeutic target for the treatment of steroid-sensitive cancers. Herein, we report the synthesis and biological evaluation of sulfamate analogs as potential STS inhibitors based on N-acylated tyramines that contain C–F bonds. The inhibitory effects of the analogs were tested using STS isolated from human placenta. Of the analogs tested, 4-(2-perfluoroundecanoylaminoethyl)-phenyl sulfamate, 5r, demonstrated the greatest inhibitory effect, with an IC50 value of 2.18?μm (IC50 value of 2.13?μm for coumarin-7-O-sulfamate was used as a reference). These findings were supported by the results our computational analyses performed using molecular docking techniques.
Synthesis, antitumor activity and mechanism of action of novel 1,3-thiazole derivatives containing hydrazide–hydrazone and carboxamide moiety
He, Haifeng,Wang, Xiaoyan,Shi, Liqiao,Yin, Wenyan,Yang, Ziwen,He, Hongwu,Liang, Ying
supporting information, p. 3263 - 3270 (2016/07/12)
A series of novel 2,4,5-trisubstituted 1,3-thiazole derivatives containing hydrazide–hydrazine, and carboxamide moiety including 46 compounds T were synthesized, and evaluated for their antitumor activity in vitro against a panel of five human cancer cell lines. Eighteen title compounds T displayed higher inhibitory activity than that of 5-Fu against MCF-7, HepG2, BGC-823, Hela, and A549 cell lines. Especially, T1, T26 and T38 exhibit best cytotoxic activity with IC50values of 2.21?μg/mL, 1.67?μg/mL and 1.11?μg/mL, against MCF-7, BCG-823, and HepG2 cell lines, respectively. These results suggested that the combination of 1,3-thiazole, hydrazide–hydrazone, and carboxamide moiety was much favorable to cytotoxicity activity. Furthermore, the flow cytometry analysis revealed that compounds T1 and T38 could induce apoptosis in HepG2 cells, and it was confirmed T38 led the induction of cell apoptosis by S cell-cycle arrest.
