- SUBSTITUTED ARYL COMPOUND AND PREPARATION METHOD THEREFOR AND USE THEREOF
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The present application relates to a substituted aryl compound or a pharmaceutically acceptable salt, a stereoisomer, a polymorph, a solvate, a N-oxide, an isotope-labeled compound, a metabolite or a prodrug thereof, and a preparation method therefor and use thereof, also relates to a pharmaceutical composition containing the compound and a therapeutic use thereof. The compound or a pharmaceutical composition thereof can inhibit the activity of adenosine A2a receptor, and can be used for treating or preventing a disease related to adenosine A2a receptor, especially for treating a tumor.
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Paragraph 0192-0193
(2021/11/04)
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- A novel class for carbonic anhydrases inhibitors and evaluation of their non-zinc binding
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In this study, 23 different imidazole derivatives were synthesized, and the inhibitory properties of these derivatives against carbonic anhydrase I and II isoenzymes were investigated for the first time. The inhibition concentrations of the imidazole derivatives were found to be in the range of 2.89–115.5 nM. Docking studies examined the binding properties of the imidazole derivatives, and the structure–activity relationship is discussed. Theoretical calculations showed that the binding mode of the imidazole ring was non-zinc binding.
- Kuzu, Burak,Tan, Meltem,Gül?in, ?lhami,Menges, Nurettin
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- Ynonylation of Acyl Radicals by Electroinduced Homolysis of 4-Acyl-1,4-dihydropyridines
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Herein we report the conversion of 4-Acyl-1,4-dihydropyridines (DHPs) into ynones under electrochemical conditions. The reaction proceeds via the homolysis of acyl-DHP under electron activation. The resulting acyl radicals react with hypervalent iodine(III) reagents to form the target ynones or ynamides in acceptable yields. This mild reaction condition allows wider functionality tolerance that includes halides, carboxylates, or alkenes. The synthetic utility of this methodology is further demonstrated by the late-stage modification of complex molecules.
- Luo, Xiaosheng,Wang, Ping
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supporting information
p. 4960 - 4965
(2021/07/20)
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- Structural Basis for EGFR Mutant Inhibition by Trisubstituted Imidazole Inhibitors
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Acquired drug resistance in epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer is a persistent challenge in cancer therapy. Previous studies of trisubstituted imidazole inhibitors led to the serendipitous discovery of inhibitors that target the drug resistant EGFR(L858R/T790M/C797S) mutant with nanomolar potencies in a reversible binding mechanism. To dissect the molecular basis for their activity, we determined the binding modes of several trisubstituted imidazole inhibitors in complex with the EGFR kinase domain with X-ray crystallography. These structures reveal that the imidazole core acts as an H-bond acceptor for the catalytic lysine (K745) in the "αC-helix out" inactive state. Selective N-methylation of the H-bond accepting nitrogen ablates inhibitor potency, confirming the role of the K745 H-bond in potent, noncovalent inhibition of the C797S variant. Insights from these studies offer new strategies for developing next generation inhibitors targeting EGFR in non-small-cell lung cancer.
- Heppner, David E.,Günther, Marcel,Wittlinger, Florian,Laufer, Stefan A.,Eck, Michael J.
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p. 4293 - 4305
(2020/05/27)
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- 1-phenyl-2-phenylaminoethyl ketone derivative and medical application
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The invention belongs to the field of pharmaceutical chemicals, and relates to a micromolecular inhibitor of polymyxin drug-resistant protein MCR-1 and application thereof. The invention relates to acompound shown as a formula I, a pharmaceutically accept
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Paragraph 0081; 0082
(2020/04/17)
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- Pyrimidine-containing tri-substituted imidazole compound and application thereof
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The invention relates to a pyrimidine-containing tri-substituted imidazole compound and application thereof. The compound has a structure shown as a formula (I). The compound can be used for effectively inhibiting EGFR (epidermal growth factor receptor) C797S mutation including EGFR ex19del/T790M/C797S and L858R/T790M/C797S; meanwhile, the compounds also have high inhibitory activity on single-point mutation L858R, ex19del and double-point mutation such as L858R/T790M, ex19del/T790M and the like, and moreover, the compounds have a weak inhibitory effect on wild EGFR (epidermal growth factor receptor), namely, the compounds have very good selectivity. The compound has potential to become a drug for treating malignant tumors carrying EGFR C797S mutation, especially non-small cell lung cancer(NSCLC), and has great application value.
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Paragraph 0218; 0221
(2020/07/15)
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- Design, synthesis and biological evaluation of 1-Phenyl-2-(phenylamino) Ethanone Derivatives as Novel MCR-1 Inhibitors
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Polymyxins are considered to be the last-line antibiotics that are used to treat infections caused by multidrug-resistant (MDR) gram-negative bacteria; however, the plasmid-mediated transferable colistin resistance gene (mcr-1) has rendered polymyxins ine
- Lan, Xiu-juan,Yan, Hai-tao,Lin, Feng,Hou, Shi,Li, Chen-chen,Wang, Guang-shu,Sun, Wei,Xiao, Jun-hai,Li, Song
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supporting information
(2019/08/07)
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- Mono- or di-substituted imidazole derivatives for inhibition of acetylcholine and butyrylcholine esterases
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Mono- or di-substituted imidazole derivatives were synthesized using a one-pot, two-step strategy. All imidazole derivatives were tested for AChE and BChE inhibition and showed nanomolar activity similar to that of the test compound donepezil and higher than that of tacrine. Structure activity relationship studies, docking studies to on X-ray crystal structure of AChE with PDB code 1B41, and adsorption, distribution, metabolism, and excretion (ADME) predictions were performed. The synthesized core skeleton was bound to important regions of the active site of AChE such as the peripheral anionic site (PAS), oxyanion hole (OH), and anionic subsite (AS). Selectivity of the reported test compounds was calculated and enzyme kinetic studies revealed that they behave as competitive inhibitors, while two of the test compounds showed noncompetitive inhibitory behavior. ADME predictions revealed that the synthesized molecules might pass through the blood brain barrier and intestinal epithelial barrier and circulate freely in the blood stream without binding to human serum albumin. While the toxicity of one compound on the WS1 (skin fibroblast) cell line was 1790 μM, its toxicity on the SH-SY5Y (neuroblastoma) cell line was 950 μM.
- Kuzu, Burak,Tan, Meltem,Taslimi, Parham,Gül?in, ?lhami,Ta?p?nar, Mehmet,Menges, Nurettin
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p. 187 - 196
(2019/02/06)
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- Exocyclic N-Acyliminium Ion (NAI) Cyclization: Access to Fully Substituted Oxazoles and Furocoumarins
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A concise, one-pot route to oxazoles and furocoumarins has been reported. The key step in this transformation involves in situ generation of N-acyliminium ion (NAI) precursor under catalyst and solvent-free conditions and their further transformations promoted by superacid in the same pot. We have also presented the experimental evidence for the involvement of proto-solvated novel exocyclic N-acyliminium ion. Further, the UV-visible and fluorescence studies revealed that few of the compounds reported here exhibited emission of blue light upon irradiation in EtOH in the region of 404-422 nm.
- Babu, Venkata Nagarjuna,Murugan, Arumugavel,Katta, Narenderreddy,Devatha, Suman,Sharada, Duddu S.
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p. 6631 - 6641
(2019/06/07)
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- Oxidative C-C Bond Cleavage for the Synthesis of Aryl Carboxylic Acids from Aryl Alkyl Ketones
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A metal-free and one-pot two-step synthesis of aryl carboxylic acids from aryl alkyl ketones has been achieved. The reactions were performed with iodine as the catalyst, DMSO and TBHP as the oxidants. Under the optimal reaction conditions, a number of aryl alkyl ketones could be converted into their corresponding aryl carboxylic acids in good to excellent yields (up to 94%).
- Xu, Liang,Wang, Shengpeng,Chen, Bajin,Li, Meichao,Hu, Xinquan,Hu, Baoxiang,Jin, Liqun,Sun, Nan,Shen, Zhenlu
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supporting information
p. 1505 - 1509
(2018/05/25)
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- Synthesis of novel imidazopyridines and their biological evaluation as potent anticancer agents: A promising candidate for glioblastoma
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Novel imidazopyridine derivatives were synthesized according to a very simple protocol and then subjected to cytotoxicity testing against LN-405 cells. Two of the compounds exhibited antiproliferative effects on LN-405 cells at 10 and 75 μM and were selected as lead compounds for further study. Safety experiment for lead compounds on WS1 was carried out and IC50 values were calculated as 480 and 844 μM. LN-405 cell line were incubated with the lead compounds and then tested for DNA damage by comet assay and effects on cell cycle using flow cytometry. The results of these two tests showed that both lead compounds affected the G0/G1 phase and did not allow the cells to reach the synthesis phase. The log BB (blood–brain barrier) and Caco-2 permeability of the synthesized molecules were calculated and it was shown that imidazopyridine derivatives taken orally are likely to pass through gastrointestinal membrane and the blood–brain barrier.
- Gü?lü, Dilek,Kuzu, Burak,Tozlu, ?srafil,Ta?p?nar, Filiz,Canp?nar, Hande,Ta?p?nar, Mehmet,Menges, Nurettin
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supporting information
p. 2647 - 2651
(2018/07/06)
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- Enantioselective Cyanosilylation of α,α-Dialkoxy Ketones by Using Phosphine-Thiourea Dual-Reagent Catalysis
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The first highly enantioselective cyanosilylation of α,α-dialkoxy ketones enabled by a dual-reagent catalysis has been developed. With the combination of a chiral bifunctional phosphine-thiourea and methyl acrylate, the key organophosphorus zwitterion intermediate was generated in situ as a novel Lewis base, which catalyzed the enantioselective cyanosilylation reaction in excellent yields (up to 99 %) with good-to-excellent enantioselectivities (up to 94 % ee).
- Yu, Qi-Wen,Wu, Lu-Ping,Kang, Tian-Chen,Xie, Jin,Sha, Feng,Wu, Xin-Yan
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supporting information
p. 3992 - 3996
(2018/07/31)
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- Direct preparation of indole hemiaminals through organocatalytic nucleophilic addition of indole to aldehydes
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Hemiaminals are common in natural products as well as bioactive compounds. Hemiaminals with an indole moiety are particularly attractive due to the significant bioactivity of indoles. Herein, we reported an efficient organocatalyzed indole N-1 nucleophilic addition of α-oxoaldehydes to deliver various indole hemiaminals in good yields (up to 92percent) and excellent regioselectivities with DABCO or triethylamine as the catalyst. The method is characterized by mild reaction conditions, widely available reagents, and general substrate scope, and it is also applicable to late-stage transformations without affecting the hemiaminal group. In addition, we carried out this reaction in an enantioselective fashion in good yields and high ee values with two general substrates.
- Chen, Zhili,Li, Yige,Qin, Wenling,Zhang, Nan
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supporting information
p. 4063 - 4070
(2018/10/15)
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- Visible-light assisted one-pot preparation of aryl glyoxals from acetoarylones via in-situ arylacyl bromides formation: Selenium-free approach to acetoarylones oxidation
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A novel visible-light (blue LEDs: hν?=?425?±?15?nm) photocatalyzed one-pot method for the synthesis of electronically diverse aryl glyoxals in good to excellent yields from acetoarylones and green regents such as air, vitamin C and dioxane dibromide has been described. In addition, an application of the current methodology has been demonstrated for the oxidation of monoamine oxidase-B inhibitors, i.e., 1-(4-((4-fluorobenzyl)oxy)phenyl)ethanone and 1-(3-((4-chlorobenzyl)oxy)phenyl)ethanone. This finding may serves as a valuable alternative to the traditional acetoarylones oxidation reactions conducted using selenium dioxide a harmful and unselective reagent known to simultaneously oxidize allylic, benzylic, [sbnd]CH3and so on.
- Natarajan, Palani,Manjeet,Kumar, Naveen,Devi, Sapna,Mer, Kalyani
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supporting information
p. 658 - 662
(2017/01/25)
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- Trisubstituted Pyridinylimidazoles as Potent Inhibitors of the Clinically Resistant L858R/T790M/C797S EGFR Mutant: Targeting of Both Hydrophobic Regions and the Phosphate Binding Site
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Inhibition of the epidermal growth factor receptor represents one of the most promising strategies in the treatment of lung cancer. Acquired resistance compromises the clinical efficacy of EGFR inhibitors during long-term treatment. The recently discovered EGFR-C797S mutation causes resistance against third-generation EGFR inhibitors. Here we present a rational approach based on extending the inhibition profile of a p38 MAP kinase inhibitor toward mutant EGFR inhibition. We used a privileged scaffold with proven cellular potency as well as in vivo efficacy and low toxicity. Guided by molecular modeling, we synthesized and studied the structure-activity relationship of 40 compounds against clinically relevant EGFR mutants. We successfully improved the cellular EGFR inhibition down to the low nanomolar range with covalently binding inhibitors against a gefitinib resistant T790M mutant cell line. We identified additional noncovalent interactions, which allowed us to develop metabolically stable inhibitors with high activities against the osimertinib resistant L858R/T790M/C797S mutant.
- Günther, Marcel,Lategahn, Jonas,Juchum, Michael,D?ring, Eva,Keul, Marina,Engel, Julian,Tumbrink, Hannah L.,Rauh, Daniel,Laufer, Stefan
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p. 5613 - 5637
(2017/07/22)
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- Novel and convenient one-pot strategy for regioselective synthesis of new 5-aryl-3-methyl-1-phenyl-1,2-dihydro-7aH-pyrazolo[3,4-c]pyridazin-7a-ol derivatives
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Abstract: We describe a novel and simple regioselective synthesis of 5-aryl-3-methyl-1-phenyl-1,2-dihydro-7aH-pyrazolo[3,4-c]pyridazin-7a-ol derivatives via one-pot three-component reaction of arylglyoxalmonohydrates, 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one, and hydrazine hydrate in presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) as base-organocatalyst at room temperature in acetonitrile. This one-pot method has the advantages of simple methodology, high atom economy, cost-effectiveness, high regioselectivity, and easy workup. Graphical Abstract: [Figure not available: see fulltext.].
- Rimaz, Mehdi,Mousavi, Hossein,Nikpey, Laya,Khalili, Behzad
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p. 3925 - 3937
(2017/06/20)
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- Synthesis of Some 5-[2-Aryl-2-oxoethyl]-1,3-dimethylpyrimidine-2,4,6-trione Derivatives by a One-pot, Three-component Reaction
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This study reports the reduction of á,a-unsaturated ketones 4a-g, formed by condensation of arylglyoxals 2a-g with 1,3-dimethylbarbituric acid (3) by L-cysteine (5) in the presence of phosphotungstic acid as a catalyst. This reaction leads to the formation of 5-[2-aryl-2-oxoethyl]-1,3-dimethylpyrimidine-2,4,6-triones 6a-g, with no sign of any heterocyclic product formation. The structure of compound 6f was confirmed by X-ray crystallography.
- Khalafy, Jabbar,Ezzati, Mahnaz,Madadi, Parinaz,Marjani, Ahmad Poursattar,Asl, Hooman Yaghoobnejad
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p. 132 - 136
(2017/11/06)
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- Synthesis of 2-acyl-benzo[1,3-d]selenazoles via domino oxidative cyclization of methyl ketones with bis(2-aminophenyl) diselenide
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A general, practical and simple one-pot synthesis of 2-acyl-benzo[1,3-d]selenazoles was developed by reacting a wide range of 2-arylethane-1,2-diones, generated in situ from commercially available aryl methyl ketones, with bis(2-aminophenyl) diselenide, promoted by Na2S2O5 in DMSO at 100 °C. Comparatively, the reactions were conducted under conventional heating and microwave irradiation. The use of focused microwave irradiation drastically decreased the reaction time from 48 to 2 h with a gain in the reaction yield for most cases. Still, 2-phenylacyl-benzo[1,3-d]selenazole was elected to react with sodium borohydride and butylmagnesium bromide, giving the respective secondary and tertiary alcohols under mild reaction conditions.
- Balaguez, Renata A.,Betin, Eduardo S.,Barcellos, Thiago,Lenard?o, Eder J.,Alves, Diego,Schumacher, Ricardo F.
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supporting information
p. 1483 - 1487
(2017/02/23)
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- Organocatalytic Enantioselective Acyloin Rearrangement of α-Hydroxy Acetals to α-Alkoxy Ketones
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We report an unprecedented organocatalytic enantioselective acyloin rearrangement of α,α-disubstituted α-hydroxy acetals. In the presence of a catalytic amount of chiral binol-derived N-triflyl phosphoramide, α-hydroxy acetals rearranged to α-alkoxy ketones in good to high yields with high enantioselectivities. Formation of an ion pair between the in situ generated oxocarbenium ion and the chiral phosphoramide anion was proposed to be responsible for the highly efficient transfer of chirality. Conditions for removal of cyclohexyl and cyclopentyl groups from the corresponding α-alkoxy ketones were uncovered underpinning their potential general utility as hydroxy protecting groups. Conversion of the rearranged products to the enantioenriched α-hydroxy ketone, 1,2-diol, β-amino alcohol and 1,4-dioxane was also documented.
- Wu, Hua,Wang, Qian,Zhu, Jieping
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supporting information
p. 5858 - 5861
(2017/05/12)
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- Iridium-Catalyzed Asymmetric Hydrogenation of Unsaturated Piperazin-2-ones
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Two different iridium catalyst systems, generated from the ruthenocene-based phosphine-oxazoline ligand tBu-mono-RuPHOX or the diphosphine ligand BINAP, were developed for the asymmetric hydrogenation of 5,6-dihydropyrazin-2(1H)-ones, affording chiral piperazin-2-ones in good yields and with moderate to good ees. Different catalytic behaviors for the hydrogenation of these types of substrate were observed with these two catalyst systems. Our tBu-mono-RuPHOX ligand, which bears a ruthenocene scaffold with planar chirality, was found to be the best ligand for the [Ir(L)(COD)]BArF catalyst system, affording the desired products with up to 94% ee. (Figure presented.).
- Wang, Yanzhao,Liu, Yuanyuan,Li, Kun,Yang, Guoqiang,Zhang, Wanbin
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supporting information
p. 1933 - 1941
(2017/06/09)
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- Trisubstituted Imidazoles with a Rigidized Hinge Binding Motif Act As Single Digit nM Inhibitors of Clinically Relevant EGFR L858R/T790M and L858R/T790M/C797S Mutants: An Example of Target Hopping
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The high genomic instability of non-small cell lung cancer tumors leads to the rapid development of resistance against promising EGFR tyrosine kinase inhibitors (TKIs). A recently detected triple mutation compromises the activity of the gold standard third-generation EGFR inhibitors. We have prepared a set of trisubstituted imidazoles with a rigidized 7-azaindole hinge binding motif as a new structural class of EGFR inhibitors by a target hopping approach from p38α MAPK inhibitor templates. On the basis of an iterative approach of docking, compound preparation, biological testing, and SAR interpretation, robust and flexible synthetic routes were established. As a result, we report two reversible inhibitors 11d and 11e of the clinically challenging triple mutant L858R/T790M/C797S with IC50 values in the low nanomolar range. Furthermore, we developed a kinome selective irreversible inhibitor 45a with an IC50 value of 1 nM against the EGFR L858R/T790M double mutant. Target binding kinetics and metabolic stability data are included. These potent mutant EGFR inhibitors may serve as a basis for the development of structurally novel EGFR probes, tools, or candidates.
- Juchum, Michael,Günther, Marcel,D?ring, Eva,Sievers-Engler, Adrian,L?mmerhofer, Michael,Laufer, Stefan
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supporting information
p. 4636 - 4656
(2017/06/13)
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- Palladium-catalyzed decarboxylative, decarbonylative and dehydrogenative C(sp2)-H acylation at room temperature
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Over the past few decades, an impressive array of C-H activation methodology has been developed for organic synthesis. However, due to the inherent inertness of the C-H bonds (e.g. ~110 kcal mol-1 for the cleavage of C(aryl)-H bonds) harsh reaction conditions have been realized to overcome high energetic transition states resulting in a limited substrate scope and functional group tolerance. Therefore, the development of mild C-H functionalization protocols is in high demand to exploit the full potential of the C-H activation strategy in the synthesis of a complex molecular framework. Although, electron-rich substrates undergo electrophilic metalation under relatively mild conditions, electron-deficient substrates proceed through a rate-limiting C-H insertion under forcing conditions at high temperature. In addition, a stoichiometric amount of toxic silver salt is frequently used in palladium catalysis to facilitate the C-H activation process which is not acceptable from the environmental and industrial standpoint. We report herein, a Pd(ii)-catalyzed decarboxylative C-H acylation of 2-arylpyridines with α-ketocarboxylic acids under mild conditions. The present protocol does not require stoichiometric silver(i) salts as additives and proceeds smoothly at ambient temperature. A novel decarbonylative C-H acylation reaction has also been accomplished using aryl glyoxals as acyl surrogates. Finally, a practical C-H acylation via a dehydrogenative pathway has been demonstrated using commercially available benzaldehydes and aqueous hydroperoxides. We also disclose that acetonitrile solvent is optimal for the acylation reaction at room temperature and has a prominent role in the reaction outcome. Control experiments suggest that the acylation reaction via decarboxylative, decarbonylative and dehydrogenative proceeds through a radical pathway. Thus we disclose a practical protocol for the sp2 C-H acylation reaction.
- Hossian, Asik,Manna, Manash Kumar,Manna, Kartic,Jana, Ranjan
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supporting information
p. 6592 - 6603
(2017/08/16)
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- Lung Cancer: EGFR Inhibitors with Low Nanomolar Activity against a Therapy-Resistant L858R/T790M/C797S Mutant
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The treatment of non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) inhibitors is made challenging by acquired resistance caused by somatic mutations. Third-generation EGFR inhibitors have been designed to overcome resistance through covalent binding to the Cys 797 residue of the enzyme, and these inhibitors are effective against most clinically relevant EGFR mutants. However, the high dependence of these recent EGFR inhibitors on this particular interaction means that additional mutation of Cys 797 results in poor inhibitory activity, which leads to tumor relapse in initially responding patients. A new generation of irreversible and reversible mutant EGFR inhibitors was developed with strong noncovalent binding properties, and these compounds show high inhibitory activities against the cysteine-mutated L858R/T790M/C797S EGFR.
- Günther, Marcel,Juchum, Michael,Kelter, Gerhard,Fiebig, Heiner,Laufer, Stefan
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supporting information
p. 10890 - 10894
(2016/09/03)
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- Rh-catalyzed asymmetric hydrogenation of racemic aldimines via dynamic kinetic resolution
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Catalyzed by a rhodium complex of P-stereogenic diphosphine ligand trichickenfootphos (TCFP), asymmetric hydrogenation of racemic aldimines via dynamic kinetic resolution has been realized for the preparation of chiral arylglycines with good yields and enantioselectivities.
- Fan, Dongyang,Lu, Jian,Liu, Yang,Zhang, Zhenfeng,Liu, Yangang,Zhang, Wanbin
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p. 5541 - 5547
(2016/08/05)
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- Novel quinoxaline based chemosensors with selective dual mode of action: Nucleophilic addition and host-guest type complex formation
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New quinoxalinium salts 1-5 have been exploited as chemosensors via naked eye, UV-Vis absorption, fluorescence quenching and 1H NMR experiments. New sensors 1-5 showed a dual mode, nucleophilic addition and a host-guest type complex towards ani
- Ishtiaq, Marium,Munir, Iqra,Al-Rashida, Mariya,Maria,Ayub, Khurshid,Iqbal, Jamshed,Ludwig, Ralf,Khan, Khalid Mohammed,Ali, Syed Abid,Hameed, Abdul
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p. 64009 - 64018
(2016/07/19)
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- Two efficient one-pot approaches for regioselective synthesis of new 3-arylpyridazino[4,3-c]quinolin-5(6H)-ones
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Two efficient regioselective approaches for the one-pot synthesis of 3-arylpyridazino[4,3-c]quinolin-5(6H)-one derivatives are reported, by the three-component reaction of arylglyoxal monohydrates, quinoline-2,4-diol, and hydrazinium dihydrochloride or hydrazine hydrate in ethanol and pyridine. In ethanol, the reactions were catalyzed by 1,4-diazobicyclo[2,2,2]octane. The features of both procedures are high regioselectivity, mild reaction conditions, good to high yields, and operational simplicity.
- Rimaz, Mehdi
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p. 1529 - 1534
(2015/10/20)
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- Regiospecific one-pot, combinatorial synthesis of new substituted pyrimido[4,5-c]pyridazines as potential monoamine oxidase inhibitors
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New 3-aryl-6-methylpyrimido[4,5-c]pyridazine-5,7(6H ,8H)-diones and 3-aryl-6-ethyl-7-thioxo-7,8-dihydropyrimido[4,5- c]pyridazin-5(6H)-ones were efficiently synthesized via a regiospecific one-pot reaction of N -methylbarbituric acid and N -ethyl-2-thiobarbituric acid with various arylglyoxal monohydrates in the presence of hydrazine dihydrochloride in ethanol at 50°C. The target compounds were obtained in high yields and were regioisomerically pure after recrystallization. These new heterocycles may act as potential MAOB inhibitors.
- Rimaz, Mehdi,Pourhossein, Paria,Khalili, Behzad
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p. 244 - 254
(2015/05/27)
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- Syntheses, Cholinesterases Inhibition, and Molecular Docking Studies of Pyrido[2,3-b]pyrazine Derivatives
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Cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), have a role in cholinergic deficit which evidently leads to Alzheimer's disease (AD). Inhibition of cholinesterases with small molecules is an attractive strategy in AD therapy. This study demonstrates synthesis of pyrido[2,3-b]pyrazines (6a-6q) series, their inhibitory activities against both cholinesterases, AChE and BChE, and molecular docking studies. The bioactivities data of pyrido[2,3-b]pyrazines showed 3-(3′-nitrophenyl)pyrido[2,3-b]pyrazine 6n a potent dual inhibitor among the series against both AChE and BChE with IC50 values of 0.466 ± 0.121 and 1.89 ± 0.05 μm, respectively. The analogues 3-(3′-methylphenyl)pyrido[2,3-b]pyrazine 6c and 3-(3′-fluorophenyl)pyrido[2,3-b]pyrazine 6f were found to be selective inhibition for BChE with IC50 values of 0.583 ± 0.052 μm and AChE with IC50 value of 0.899 ± 0.10 μm, respectively. Molecular docking studies of the active compounds suggested the putative binding modes with cholinesterases. The potent compounds among the series could potentially serves as good leads for the development of new cholinesterase inhibitors. A series of pyrido[2,3-b]pyrazine (6a-6q) derivatives has been synthesized and evaluated for inhibitory activities against cholinesterases; acetylcholinesterase, and butyrylcholinesterase. Molecular docking of active compounds was also performed to suggest the putative binding modes with cholinesterases.
- Hameed, Abdul,Zehra, Syeda T.,Shah, Syed J. A.,Khan, Khalid M.,Alharthy, Rima D.,Furtmann, Norbert,Bajorath, Jürgen,Tahir, Muhammad N.,Iqbal, Jamshed
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p. 1115 - 1120
(2015/10/28)
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- One-pot three-component reactions of methyl ketones, phenols and a nucleophile: An expedient way to synthesize densely substituted benzofurans
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Three-component reactions of phenylglyoxal monohydrate, phenols, and indoles were developed with the aid of acid-catalyst, which produced various densely substituted benzofurans with good to excellent yields. On the basis of this observation, a one-pot, step-wise reaction was developed by using methyl ketones instead of using phenylglyoxal component in I2/DMSO system. At last, three-component reaction offered a useful way to synthesize densely substituted benzofurans starting from simple and easily available substrates. The indole component can be replaced by some other nucleophiles, such as 1,2,4-trimethoxybenzene and thiophenol.
- Cheng, Cheng,Liu, Changhui,Gu, Yanlong
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p. 8009 - 8017
(2015/12/31)
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- A convenient and mild synthesis of new 2-aryl-3-hydroxy-6,7-dihydro-1H- indol-4(5H)-ones via a one-pot, three-component reaction in water
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A simple and convenient synthesis of 2-aryl-3-hydroxy-6,7-dihydro-1H-indol- 4(5H)-ones is achieved in high yields via the one-pot, three-component reaction of arylglyoxals, 1,3-cyclohexanedione, and ammonium acetate in water under reflux conditions.
- Khalafy, Jabbar,Etivand, Nasser,Dilmaghani, Shadi,Ezzati, Mahnaz,Marjani, Ahmad Poursattar
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p. 3781 - 3783
(2014/07/07)
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- Quinoxaline derivatives: Novel and selective butyrylcholinesterase inhibitors
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Alzheimer's disease (AD) is a progressive brain disorder which occurs due to lower levels of acetylcholine (ACh) neurotransmitters, and results in a gradual decline in memory and other cognitive processes. Acetycholinesterase (AChE) and butyrylcholinesterase (BChE) are considered to be primary regulators of the ACh levels in the brain. Evidence shows that AChE activity decreases in AD, while activity of BChE does not change or even elevate in advanced AD, which suggests a key involvement of BChE in ACh hydrolysis during AD symptoms. Therefore, inhibiting the activity of BChE may be an effective way to control AD associated disorders. In this regard, a series of quinoxaline derivatives 1-17 was synthesized and biologically evaluated against cholinesterases (AChE and BChE) and as well as against achymotrypsin and urease. The compounds 1-17 were found to be selective inhibitors for BChE, as no activity was found against other enzymes. Among the series, compounds 6 (IC50 = 7.7 ± 1.0μM) and 7 (IC50 = 9.7 ± 0.9 μM) were found to be the most active inhibitors against BChE. Their IC50 values are comparable to the standard, galantamine (IC50 = 6.6 ± 0.38 μM). Their considerable BChE inhibitory activity makes them selective candidates for the development of BChE inhibitors. Structure-activity relationship (SAR) of this new class of selective BChE inhibitors has been discussed.
- Zeb, Aurang,Hameed, Abdul,Khan, Latifullah,Khan, Imran,Dalvandi, Kourosh,Choudhary, M. Iqbal,Basha, Fatima Z.
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p. 724 - 729
(2015/04/14)
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- PYRIDOPYRAZINES AS ANTICANCER AGENTS
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The present invention relates to pyridopyrazine derivatives and solvates, hydrates and pharmaceutically acceptable salts thereof, the use of them in the prevention and/or the treatment of cancer diseases, as well as pharmaceutical compositions containing at least one of them as pharmaceutically active agent(s) together with pharmaceutically acceptable carrier, excipient and/or diluents, especially for the prevention and/or treatment of cancer diseases.˙
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Page/Page column 13
(2014/07/22)
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- Design and synthesis of 2-acylbenzothiazoles via in situ cross-trapping strategy from benzothiazoles with aryl ketones
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An I2/KOH synergistically promoted direct ring-opening aroylation of benzothiazoles with aryl ketones has been discovered. Aryl ketones were seen to act as carbonyl sources to construct 2-acylbenzothiazoles. This reaction could provide an example for the convergent integration of self-labor domino sequences based on an in situ cross-trapping strategy.
- Gao, Qinghe,Wu, Xia,Jia, Fengcheng,Liu, Meicai,Zhu, Yanping,Cai, Qun,Wu, Anxin
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p. 2792 - 2797
(2013/04/24)
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- A simple three-component synthesis of 3-amino-5-arylpyridazine-4- carbonitriles
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New 3-amino-5-arylpyridazine-4-carbonitriles have been synthesized by a one-pot three-component reaction of malononitrile with arylglyoxals in the presence of hydrazine hydrate at room temperature in water and ethanol.
- Khalafy,Rimaz,Farajzadeh,Ezzati
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p. 179 - 182
(2013/07/26)
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- An efficient one-pot protocol for regioselective synthesis of 3-aryl-6,8-dialkyl-7-thioxo-7,8-dihydropyrimido[4,5-c ] pyridazine-5(6 H)-ones
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A series of 3-aryl-6,8-dialkyl-7-thioxo-7,8-dihydropyrimido[4,5-c] pyridazine-5(6H)-one derivatives have been regioselectively synthesized via the one-pot three-component reaction of 1,3-dimethylthiobarbituric acid and 1,3-diethylthiobarbituric acid with various arylglyoxals in the presence of hydrazinium dihydrochloride in warm ethanol. These new substituted pyrimidopyridazines may be potential monoamine oxidase inhibitors.
- Khalafy, Jabbar,Rimaz, Mehdi,Rabiei, Hossein,Panahi, Leila
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p. 395 - 406
(2013/09/23)
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- [1,2,4]TRIAZOLO[4,3-B][1,2,4]TRIAZINE COMPOUND, PREPARATION METHOD AND USE THEREOF
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The present invention relates to a structurally novel [1,2,4]triazolo[4,3-b][1,2,4]triazine compounds represented by formula (I) or formula (II), pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof, and also relates to a preparation method of the compounds, a pharmaceutical composition comprising a therapeutically effective amount of the compounds, as well as the use thereof as protein tyrosine kinase inhibitors, particularly as c-Met inhibitors, in the preparation of medicaments for the prevention and/or treatment of diseases associated with c-Met abnormality.
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Paragraph 0271; 0272
(2013/11/05)
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- A multipathway coupled domino strategy: Metal-free oxidative cyclization for one-pot synthesis of 2-acylbenzothiazoles from multiform substrates
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A multipathway coupled domino strategy has been developed for the efficient synthesis of 2-acylbenzothiazoles from multiform substrates arylethenes, arylacetylenes, 2-hydroxy-aromatic ketones, and carbinols via four distinct pathways. Through a logical coupled oxidation/heterocyclization domino process, a variety of 2-acylbenzothiazoles were synthesized free of metal in one pot.
- Zhu, Yan-Ping,Jia, Feng-Cheng,Liu, Mei-Cai,Wu, An-Xin
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p. 4414 - 4417
(2012/10/29)
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- Synthesis of trisubstituted isoxazoles via in situ trapping strategy from α-nitro carbonyl compounds and methyl ketones or terminal aryl alkenes
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A highly efficient domino method for the synthesis of trisubstituted isoxazoles has been established from α-nitro carbonyl compounds and methyl ketones or terminal aryl alkenes. Simple and readily available starting materials, mild reaction conditions and very simple operation are significant advantages of the reaction.
- Yang, Yan,Gao, Meng,Deng, Cong,Zhang, Dong-Xue,Wu, Liu-Ming,Shu, Wen-Ming,Wu, An-Xin
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supporting information; experimental part
p. 6257 - 6262
(2012/08/28)
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- 1,2,4-TRIAZINE-4-AMINE DERIVATIVES
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According to the invention there is provided a compound of formula A1 which may be useful in the treatment of a condition or disorder ameliorated by the inhibition of the A1- A2b or, particularly, the A2a receptor wherein the compound of formula A1 has the structure, wherein, A represents Cy1 or HetA; Cy1 represents a 5- to 14-membered aromatic, fully saturated or partially unsaturated carbocyclic ring system comprising one, two or three rings, which Cy1 group is optionally substituted by one or more R4a substituents; HetA represents a 5- to 14-membered heterocyclic group that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N, which heterocyclic group may comprise one, two or three rings and which HetA group is optionally substituted by one or more R4b substituents; B represents a Cy2 or HetB; Cy2 represents a 3- to 10-membered aromatic, fully saturated or partially unsaturated carbocyclic ring system comprising one or two rings, which Cy2 group is optionally substituted by one or more R4c substituents; HetB represents a 3- to 10-membered heterocyclic group that may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N, which heterocyclic group may comprise one or two rings and which HetB group is optionally substituted by one or more R4d substituents.
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Page/Page column 94
(2011/09/14)
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- Microwave-assisted selenium dioxide oxidation of aryl methyl ketones to aryl glyoxals
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We report an improved procedure for the synthesis of phenyl glyoxal and a series of para-substituted aryl glyoxals by microwave-assisted selenium dioxide oxidation. The reaction time has been reduced from several hours to three minutes for activated aryl methyl ketone substrates and 18 min for deactivated substrates, with all reactions affording quantitative conversion into the corresponding aryl glyoxals.
- Young, Ryan M.,Davies-Coleman, Michael T.
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experimental part
p. 4036 - 4038
(2011/08/09)
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- One-pot synthesis of enantiomerically pure 1, 2-diols: Asymmetric reduction of aromatic α-oxoaldehydes catalysed by Candida parapsilosis ATCC 7330
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A facile and simple one-pot method was developed to produce a series of optically active (S)-1-phenyl-1,2-ethanediols with good yields (up to 70%) and high enantiomeric excess (>99%) via asymmetric reduction of various substituted aromatic α-oxoaldehydes using Candida parapsilosis ATCC 7330.
- Mahajabeen, Pula,Chadha, Anju
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experimental part
p. 2156 - 2160
(2012/05/04)
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- A regiospecific One-Pot, Three component synthesis of 4-Aryl-6,8- dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones as New potential monoamine oxidase inhibitors
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A series of new 4-aryl-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)- diones have been synthesized via three component reaction of 1,3-dimethylbarbituric acid with arylglyoxals in the presence of hydrazinium dihydrochloride in ethanol. All of these derivatives may act as potential monoamine oxidase inhibitors.
- Khalafy, Jabbar,Rimaz, Mehdi,Panahi, Leila,Rabiei, Hossein
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scheme or table
p. 2428 - 2432
(2012/06/01)
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- New heteroaromatic aminations on 5-aryl-1,2,4-triazines and 1,2,4,5-tetrazines by palladium catalysis
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The efficient and original palladium-catalyzed amination of 5-Aryl-1,2,4-triazines and 1,2,4,5-tetrazines is reported. This Buchwald-Hartwig type reaction leads to the formation of aminated heterocycles via methylsulfur release. The reaction is optimized and a wide range of amines is used to determine the scope and limitations of this methodology.
- Pellegatti, Laurent,Vedrenne, Emeline,Leger, Jean-Michel,Jarry, Christian,Routier, Sylvain
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experimental part
p. 4383 - 4389
(2010/07/05)
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- Synthesis of new 2-aryl-4-chloro-3-hydroxy-1H-indole-5,7-dicarbaldehydes via Vilsmeier-Haack reaction
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(Chemical Equation Presented) New 2-aryl-4-chloro-3-hydroxy-1H-indole-5,7- dicarbaldehydes were synthesized in three steps from acetophenone derivatives. By oxidation of acetophenones to aryl glyoxals using selenium dioxide and condensation with acetylacetone in the presence of ammonium acetate in water 3-acetyl-5-aryl-4-hydroxy-2-methyl-1H-pyrrols were obtained. 2-Aryl-4-chloro-3-hydroxy-1H-indole-5,7-dicarbaldehydes were synthesized via Vilsmeier-Haack reaction of pyrrole derivatives in moderate yields.
- Eftekhari-Sis, Bagher,Zirak, Maryam,Akbari, Ali,Hashemi, Mohammed M.
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scheme or table
p. 463 - 467
(2010/06/21)
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- A simple one-pot, three component synthesis of 3-arylpyrimido[4,5-c] pyridazine-5,7(6h,8h)-diones and their sulfur analogues as potential monoamine oxidase inhibitors
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Several new 3-arylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones and 3-aryl-5-oxo-7-thioxo-7,8-dihydropyrimido[4,5-c]pyridazin-5(6H)-ones have been synthesized by a three-component reaction of barbituric acid or thiobarbituric acid with arylglyoxals in the presence of a catalytic amount of pyridine and hydrazine hydrate at room temperature in water.
- Rimaz, Mehdi,Khalafy, Jabbar,Pesyan, Nader Noroozi,Prager, Rolf H.
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scheme or table
p. 507 - 510
(2010/07/15)
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- A novel one-pot, three-component synthesis of alkyl 6-aryl-3- methylpyridazine-4-carboxylates in water
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A series of new alkyl 6-aryl-3-methylpyridazine-4-carboxylates were efficiently synthesized by a three-component reaction of β-ketoesters with arylglyoxals in the presence of hydrazine hydrate in water at room temperature. ARKAT USA, Inc.
- Rimaz, Mehdi,Khalafy, Jabbar
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scheme or table
p. 110 - 117
(2010/08/04)
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- A regioselective one-pot, three component synthesis of 6-Aryl-4-cyano-3(2H) -pyridazinones in water
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A series of 4-cyano-3(2H)-pyridazinones bearing different aryl substituents in the 6-position of the pyridazinone ring was synthesized regioselectively using a novel efficient one-pot three component reaction of alkyl 2-cyanoacetates with arylglyoxals in the presence of hydrazine hydrate at room temperature in water. CSIRO 2010.
- Rimaz, Mehdi,Khalafy, Jabbar,Moghadam, Peyman Najafi
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scheme or table
p. 1396 - 1401
(2011/04/16)
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- Novel one-pot synthesis of (4 or 5)-aryl-2-aryloyl-(1H)-imidazoles in water and tauto-isomerization study using NMR
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A simple and green route to synthesis of (4 or 5)-aryl-2-aryloyl-(1H)-imidazoles is described. Two isomers can tautomerize to each other by the heat absorption. The tauto-isomerization process was studied by NMR technique. Acidity and stability of products were studied using B3LYP method.
- Khalili, Behzad,Tondro, Tahereh,Hashemi, Mohammed M.
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supporting information; experimental part
p. 6882 - 6887
(2009/12/06)
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- Novel one-pot, three-component synthesis of new 2-alkyl-5-aryl-(1H)- pyrrole-4-ol in water
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(Chemical Equation Presented) New 2-alkyl-5-aryl-(1H)-pyrrole-4-ol derivatives were synthesized via three-component reaction of β-dicarbonyl compounds with arylglyoxals in the presence of ammonium acetate in water at room temperature.
- Khalili, Behzad,Jajarmi, Pedram,Eftekhari-Sis, Bagher,Hashemi, Mohammed M.
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p. 2090 - 2095
(2008/09/18)
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- NOVEL INHIBITORS OF TYROSINASE, THEIR METHOD OF PREPARATION AND THEIR USE IN HUMAN MEDICINE AND IN COSMETICS
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The present invention relates to novel compounds corresponding to the following general formula (I): to compositions containing them, and to their use in pharmaceutical compositions intended for use in human or veterinary medicine, or alternatively in cosmetic compositions.
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Page/Page column 16
(2008/06/13)
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