5437-98-9Relevant articles and documents
Ru-NHC-Catalyzed Asymmetric Hydrogenation of 2-Quinolones to Chiral 3,4-Dihydro-2-Quinolones
Daniliuc, Constantin,Glorius, Frank,Hu, Tianjiao,Lückemeier, Lukas
supporting information, p. 23193 - 23196 (2021/09/25)
Direct enantioselective hydrogenation of unsaturated compounds to generate chiral three-dimensional motifs is one of the most straightforward and important approaches in synthetic chemistry. We realized the Ru(II)-NHC-catalyzed asymmetric hydrogenation of 2-quinolones under mild reaction conditions. Alkyl-, aryl- and halogen-substituted optically active dihydro-2-quinolones were obtained in high yields with moderate to excellent enantioselectivities. The reaction provides an efficient and atom-economic pathway to construct simple chiral 3,4-dihydro-2-quinolones. The desired products could be further reduced to tetrahydroquinolines and octahydroquinolones.
HFIP-mediated strategy towards β-oxo amides and subsequent Friedel-Craft type cyclization to 2?quinolinones using recyclable catalyst
Kabi, Arup K.,Gujjarappa, Raghuram,Vodnala, Nagaraju,Kaldhi, Dhananjaya,Tyagi, Ujjawal,Mukherjee, Kalisadhan,Malakar, Chandi C.
supporting information, (2020/10/20)
A simple and cost-effective 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)-mediated protocol for the synthesis of β-oxo amides has been described by using amines and β-keto esters as substrates. The reaction conditions were found to be highly efficient towards the cleavage of C[sbnd]O bond and consequent formation of the products in excellent yields and selectivity. The obtained β-oxo amides were further transformed in to the synthetically useful 2?quinolinones via intramolecular Friedel-Craft type cyclization of aromatic ring using ferrites as a recyclable catalyst. A spectrum of substrates bearing broad range of functional groups were well tolerated under the reaction conditions. The proposed mechanistic pathways were substantially verified by literature and mass-spectroscopic evidences.
Virtual screening and optimization of novel mTOR Inhibitors for Radiosensitization of Hepatocellular Carcinoma
Cao, Shuang,Chen, Jian-Chao,Chen, Yong-Shou,Feng, Ying-Qi,Gao, Xu-Dong,Gu, Shuang-Xi,Lu, Yin-Ying,Ren, Yi-Xin,Zhang, Heng
, p. 1779 - 1798 (2020/06/21)
Background: Radiotherapy has an ameliorative effect on a wide variety of tumors, but hepatocellular carcinoma (HCC) is insensitive to this treatment. Overactivated mammalian target of rapamycin (mTOR) plays an important part in the resistance of HCC to radiotherapy; thus, mTOR inhibitors have potential as novel radiosensitizers to enhance the efficacy of radiotherapy for HCC. Methods: A lead compound was found based on pharmacophore modeling and molecular docking, and optimized according to the differences between the ATP-binding pockets of mTOR and PI3K. The radiosensitizing effect of the optimized compound (2a) was confirmed by colony formation assays and DNA double-strand break assays in vitro. The discovery and preclinical characteristics of this compound are described. Results: The key amino acid residues in mTOR were identified, and a precise virtual screening model was constructed. Compound 2a, with a 4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine scaffold, exhibited promising potency against mTOR (mTOR IC50=7.1 nmol/L (nM)) with 126-fold selectivity over PI3Kα.Moreover, 2a significantly enhanced the sensitivity of HCC to radiotherapy in vitro in a dose-dependent manner. Conclusion: A new class of selective mTOR inhibitors was developed and their radiosensitization effects were confirmed. This study also provides a basis for developing mTORspecific inhibitors for use as radiosensitizers for HCC radiotherapy.
5-Aminothiophene-2,4-dicarboxamide analogues as hepatitis B virus capsid assembly effectors
Tang, Jing,Huber, Andrew D.,Pineda, Dallas L.,Boschert, Kelsey N.,Wolf, Jennifer J.,Kankanala, Jayakanth,Xie, Jiashu,Sarafianos, Stefan G.,Wang, Zhengqiang
supporting information, p. 179 - 192 (2019/01/04)
Chronic hepatitis B virus (HBV) infection represents a major health threat. Current FDA-approved drugs do not cure HBV. Targeting HBV core protein (Cp) provides an attractive approach toward HBV inhibition and possibly infection cure. We have previously identified and characterized a 5-amino-3-methylthiophene-2,4-dicarboxamide (ATDC) compound as a structurally novel hit for capsid assembly effectors (CAEs). We report herein hit validation through studies on absorption, distribution, metabolism and excretion (ADME) properties and pharmacokinetics (PK), and hit optimization via analogue synthesis aiming to probe the structure-activity relationship (SAR) and structure-property relationship (SPR). In the end, these medicinal chemistry efforts led to the identification of multiple analogues strongly binding to Cp, potently inhibiting HBV replication in nanomolar range without cytotoxicity, and exhibiting good oral bioavailability (F). Two of our analogues, 19o (EC50 = 0.11 μM, CC50 > 100 μM, F = 25%) and 19k (EC50 = 0.31 μM, CC50 > 100 μM, F = 46%), displayed overall lead profiles superior to reported CAEs 7–10 used in our studies.
Gold-Catalyzed Dearomative Spirocyclization of N-Aryl Alkynamides for the Synthesis of Spirolactams
Vacala, Taylor L.,Carlson, Paul R.,Arreola-Hester, Asa,Williams, Chloé G.,Makhoul, Evana W.,Vadola, Paul A.
, p. 1493 - 1501 (2018/02/10)
A catalytic redox-neutral method for the synthesis of spirolactams proceeding through the dearomative spirocyclization of N-aryl alkynamides is reported. In contrast to stoichiometric activating agents employed for related transformations, we show that the use of 5 mol % of Au(PPh3)Cl and AgOTf in dichloroethane at 50-80 °C leads to selective spirocyclization, furnishing the products in yields of 35-87%. The substrate scope of the reaction is good, with both electron-donating and electron-withdrawing groups being tolerated around the arene ring, as well as substitution at the amide nitrogen. The identity of the para-alkoxy group on the arene ring is key to achieving selectivity for spirocyclization over alternative mechanistic pathways. While the presence of a para-methoxy group leads to trace amounts of the desired spirolactams, the para-tert-butoxy or para-hydroxy substrate analogues furnish the spirolactams in good yield with high selectivity.
Novel 5-oxo-hexahydroquinoline derivatives: Design, synthesis, in vitro P-glycoprotein-mediated multidrug resistance reversal profile and molecular dynamics simulation study
Shahraki, Omolbanin,Edraki, Najmeh,Khoshneviszadeh, Mehdi,Zargari, Farshid,Ranjbar, Sara,Saso, Luciano,Firuzi, Omidreza,Miri, Ramin
, p. 407 - 418 (2017/02/26)
Overexpression of the efflux pump P-glycoprotein (P-gp) is one of the important mechanisms of multidrug resistance (MDR) in many tumor cells. In this study, 26 novel 5-oxo-hexahydroquinoline derivatives containing different nitrophenyl moieties at C4 and various carboxamide substituents at C3 were designed, synthesized and evaluated for their ability to inhibit P-gp by measuring the amount of rhodamine 123 (Rh123) accumulation in uterine sarcoma cells that overexpress P-gp (MES-SA/Dx5) using flow cytometry. The effect of compounds with highest MDR reversal activities was further evaluated by measuring the alterations of MES-SA/Dx5 cells’ sensitivity to doxorubicin (DXR) using MTT assay. The results of both biological assays indicated that compounds bearing 2-nitrophenyl at C4 position and compounds with 4-chlorophenyl carboxamide at C3 demonstrated the highest activities in resistant cells, while they were devoid of any effect in parental nonresistant MES-SA cells. One of the active derivatives, 5c, significantly increased intracellular Rh123 at 100 μM, and it also significantly reduced the IC50 of DXR by 70.1% and 88.7% at 10 and 25 μM, respectively, in MES-SA/Dx5 cells. The toxicity of synthesized compounds against HEK293 as a noncancer cell line was also investigated. All tested derivatives except for 2c compound showed no cytotoxicity. A molecular dynamics simulation study was also performed to investigate the possible binding site of 5c in complex with human P-gp, which showed that this compound formed 11 average H-bonds with Ser909, Thr911, Arg547, Arg543 and Ser474 residues of P-gp. A good agreement was found between the results of the computational and experimental studies. The findings of this study show that some 5-oxo-hexahydroquinoline derivatives could serve as promising candidates for the discovery of new agents for P-gp-mediated MDR reversal.
Effective microwave synthesis of bioactive thieno[2,3-d]pyrimidines
Khatri, Taslimahemad T.,Shah, Viresh H.
, p. 3354 - 3358 (2017/05/22)
A series of novel 2-Amino-3-cyanothiophenes (2a-2j) were synthesized using heterogeneous base (K2CO3) supported Gewald reaction. Cyclization of 2a-j with formamide and urea in conventional heating as well as microwave irradiation gave thieno[2,3-d]pyrimidines (3a-3j) and thieno[2,3-d]pyrimidin-2(1H)-ones(4a-4j) respectively. The reaction rates were faster and yields were higher in the microwave conditions. The structures of the compounds were confirmed with elemental analysis, mass spectral analysis, FTIR, 1H NMR and 13C NMR techniques. All the synthesized compounds were subjected to antimicrobial activity (MIC) in vitro by broth dilution method and exhibited a moderate antimicrobial activity.
Compounds having anticonvulsion activity, preparing methods thereof and applications of the compounds
-
Paragraph 0041; 0042; 0043; 0044, (2017/10/05)
The invention provides 7-substituted-5-methyl-1,2,4-triazolo[4,3-a] quinoline and 7-substituted-5-ethoxy-[1,2,4]-triazolo[4,3-a] quinoline compounds having anticonvulsion activity, preparing methods thereof and applications of the compounds in the field of preparing anticonvulsion medicines.
Design and synthesis of novel coumarin analogs and their nematicidal activity against five phytonematodes
Pan, Le,Li, Xiu-Zhuang,Sun, Di-An,Jin, Hui,Guo, Hong-Ru,Qin, Bo
supporting information, p. 375 - 379 (2016/03/19)
The presence of hydroxyl groups at the C4 and C7 positions in coumarin backbone has been proposed as a potential modification site for providing excellent bioactivity according to previous studies. A series of novel coumarin derivatives were rationally designed and synthesized by use of a complex catalytic system for a targeted modification at the above sites. These derivatives were assayed for nematicidal activity. As predicted, the derivatization enhanced the activity of the coumarins against five nematodes. Compounds 7b, 9a, 10c and 11c showed significant strong nematicidal broad spectrum activity against all tested nematodes. Compound 10c was the most effective with the lowest LC50 values against Meloidogyne incognita (5.1 μmol/L), Ditylenchus destructor (3.7 μmol/L), Bursaphelenchus mucronatus (6.4 μmol/L), Bursaphelenchus B. xylophilus (2.5 μmol/L) and Aphelenchoides besseyi (3.1 μmol/L), respectively. A brief investigation on the structure-activity relationships (SAR) revealed that the targeted modification by a C7 hydroxyl was optimum compared with that of a C4 hydroxyl and that the coupling chain length was crucial for the nematicidal activity.
Design, Multicomponent Synthesis and Characterization of Diversely Substituted Pyrazolo[1,5-a] Pyrimidine Derivatives
Ghelani, Satish M.,Naliapara, Yogesh T.
, p. 1843 - 1851 (2016/11/23)
The synthesis of various heterocyclic compounds using acetoacetanilide[AAA], we have demonstrated that acetoactanilide are versatile intermediate for the synthesis of pyrazolopyrimidine derivatives. Thus, to explore further, we sought that the reaction of various acetoactanilide, an appropriate aldehyde and 5-amino-N-cyclohexyl-3-(methylthio)-1H-pyrazole-4-carboxamide in the presence of base in isopropyl alcohol could be an effective strategy to furnish the novel pyrazolopyrimidine derivatives. Here we describe the novel synthetic methodology for the fused pyrazolopyrimidines.
