- One-Pot Total Synthesis of Evodiamine and Its Analogues through a Continuous Biscyclization Reaction
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The one-pot total synthesis of evodiamine and its analogues is achieved using a three-component reaction. Through continuous biscyclization, various readily available substrates with good functional group tolerance were easily incorporated into biologically active quinazolinocarboline backbones. The use of triethoxymethane as a cosolvent was crucial for this quick and straightforward transformation.
- Wang, Zi-Xuan,Xiang, Jia-Chen,Wang, Miao,Ma, Jin-Tian,Wu, Yan-Dong,Wu, An-Xin
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- Design, synthesis and docking studies of novel 1,2-dihydro-4-hydroxy-2-oxoquinoline-3-carboxamide derivatives as a potential anti-proliferative agents
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A new series of 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide hybrids 8a-l have been designed and synthesized using peptide coupling agents with substituted N-phenyl piperazines and piperidines with good to excellent yields. The synthesized compounds were evaluated for their in?vitro anti-proliferative activity against PANC 1, HeLa and MDA-MB-231. The compounds 8d, 8e, 8f, 8g, 8h and 8k exhibited considerable anti-proliferative activity with GI50values ranging from 0.15 to 1.4?μM. The structure and anti-proliferative activity relationship was further supported by in silico molecular docking study of the active compounds against tubulin protein.
- Banu, Saleha,Bollu, Rajitha,Bantu, Rajashaker,Nagarapu, Lingaiah,Polepalli, Sowjanya,Jain, Nishant,Vangala, Radhika,Manga, Vijjulatha
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- Discovery of Evodiamine Derivatives as Highly Selective PDE5 Inhibitors Targeting a Unique Allosteric Pocket
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Clinical use of phosphodiesterase-5 (PDE5) inhibitors is limited by several side effects due to weak isoform selectivity. Herein, a unique allosteric pocket of PDE5 is identified by molecular modeling and structural biology, which enables the discovery of highly selective PDE5 inhibitors from natural product evodiamine (EVO). The crystal structure of PDE5 with bound EVO derivative (S)-7e revealed that binding of (S)-7e to the novel allosteric pocket induced dramatic conformation changes in the H-loop with a maximum 24 ? movement of their Cα atoms. This movement directly blocks the binding of substrate/inhibitors to the PDE5 active site, which is different from all traditional PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil. These derivatives showed >570-fold selectivity over PDE6C and PDE11A and achieved potent efficacy for the effective treatment of pulmonary hypertension in vivo.
- Zhang, Tianhua,Lai, Zengwei,Yuan, Suying,Huang, Yi-You,Dong, Guoqiang,Sheng, Chunquan,Ke, Hengming,Luo, Hai-Bin
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- Synthesis, regioselectivity, and DFT analysis of new antioxidant pyrazolo[4,3-c]quinoline-3,4-diones
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The condensation of hydrazine, N-methylhydrazine, and N-phenylhydrazine with ethyl 4-chloro-2-oxo- 1,2-dihydroquinoline-3-carboxylate derivatives has been investigated. As a result, 12 new antioxidant pyrazolo[4,3- c]quinolin-3,4-diones were obtained with good to high yields. When two cross-products could be possible, only one isomer bearing the methyl or the phenyl group at the N1 position is isolated and unequivocally characterized using 1D and 2D NMR techniques, FT-IR, and combustion analyses. DFT analysis of the reaction mechanism was carried out in the Pearson’s hard soft acid base framework, confirming the assigned structure to the observed pyrazolo[4,3-c]quinolin-3,4-diones. These calculations indicate a favored kinetic control for the synthesized pyrazolo[4,3- c]quinolin-3,4-diones compared to its possible regioisomer.
- Tomassoli, Isabelle,Herlem, Guillaume,Picaud, Fabien,Benchekroun, Mohamed,Bautista-Aguilera, Oscar M.,Luzet, Vincent,Jimeno, María-Luisa,Gharbi, Tijani,Refouvelet, Bernard,Ismaili, Lhassane
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- Synthesis and antimicrobial activity of novel 4-Hydroxy-2-quinolone analogs
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Alkyl quinolone has been proven to be a privileged scaffold in the antimicrobial drug discovery pipeline. In this study, a series of new 4-hydroxy-2-quinolinone analogs containing a long alkyl side chain at C-3 and a broad range of substituents on the C-6 and C-7 positions were synthesized. The antibacterial and antifungal activities of these analogs against Staphylococcus aureus, Escherichia coli, and Aspergillus flavus were investigated. The structure-activity relationship study revealed that the length of the alkyl chain, as well as the type of substituent, has a dramatic impact on the antimicrobial activities. Particularly, the brominated analogs 3j with a nonyl side chain exhibited exceptional antifungal activities against A. flavus (half maximal inhibitory concentration (IC50) = 1.05 μg/mL), which surpassed that of the amphotericin B used as a positive control. The antibacterial activity against S. aureus, although not as potent, showed a similar trend to the antifungal activity. The data suggest that the 4-hydroxy-2-quinolone is a promising framework for the further development of new antimicrobial agents, especially for antifungal treatment.
- Khamkhenshorngphanuch, Thitiphong,Kulkraisri, Kittipat,Janjamratsaeng, Alongkorn,Plabutong, Napasawan,Thammahong, Arsa,Manadee, Kanitta,Na Pombejra, Sarisa,Khotavivattana, Tanatorn
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- Design, Synthesis, and in vitro antitubercular activity of 1,2,3-triazolyl-dihydroquinoline derivatives
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In the quest for new active molecules against Mycobacterium tuberculosis, a series of dihydroquinoline derivatives possessing triazolo substituents were efficiently synthesized using click chemistry. The structure of 6l was evidenced by X-ray crystallographic study. The newly synthesized compounds were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv (ATCC27294). The compounds 6a, 6g, and 6j (MIC: 3.13?μg/ml) showed promising activity when compared to the first-line drug such as ethambutol. In addition, the structure and antitubercular activity relationship were further supported by in silico molecular docking studies of the active compounds against 3IVX.PDB (crystal structure of pantothenate synthetase in complex with 2-(2-(benzofuran-2-ylsulfonylcarbamoyl)-5-methoxy-1H-indol-1-yl)acetic acid).
- Banu, Saleha,Bollu, Rajitha,Nagarapu, Lingaiah,Nanubolu, Jagadeesh Babu,Yogeswari, Perumal,Sriram, Dharmarajan,Gunda, Shravan Kumar,Vardhan, Divyasphoorthi
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- A novel templates of piperazinyl-1,2-dihydroquinoline-3-carboxylates: Synthesis, anti-microbial evaluation and molecular docking studies
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A series of piperazinyl-1,2-dihydroquinoline carboxylates were synthesized by the reaction of ethyl 4-chloro-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylates with various piperazines and their structures were confirmed by 1H NMR, 13C NMR, IR and mass spectral analysis. All the synthesized compounds were screened for their in vitro antimicrobial activities. Further, the in silico molecular docking studies of the active compounds was performed to explore the binding interactions between piperazinyl-1,2-dihydroquinoline carboxylate derivatives and the active site of the Staphylococcus aureus (CrtM) dehydrosqualene synthase (PDB ID: 2ZCQ). The docking studies revealed that the synthesized derivatives showed high binding energies and strong H-bond interactions with the dehydrosqualene synthase validating the observed antimicrobial activity data. Based on antimicrobial activity and docking studies, the compounds 9b and 10c were identified as promising antimicrobial lead molecules. This study might provide insights to identify new drug candidates that target the S. aureus virulence factor, dehydrosqualene synthase.
- Banu, Saleha,Bollu, Rajitha,Naseema, Mohammad,Gomedhika, P. Mary,Nagarapu, Lingaiah,Sirisha,Kumar, C. Ganesh,Gundasw, Shravan Kumar
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- Electrosynthesis of N-methylisatin
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Isatin in a solution of dry N,N-dimethylformamide/NaClO4 is electroreduced in the presence of CH3I. N-methylisatin (NMI) is obtained in quantitative molar yield and high current efficiency by controlled potential electrolysis (CPE). NMI and N-methylisatoic anhydride are the reaction products when CPE is performed in the absence of CH3I, but adding it once the CPE was completed. The water effect on the identity and yield of the reaction product(s) is investigated. Reaction pathways are proposed.
- Martínez Suárez, Jaime F.,Caram, José A.,Echeverriá, Gustavo. A.,Piro, Oscar E.,Gennaro, Ana. M.,Mirífico, Mariá. V.
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- One-step Synthesis for the Preparation of Quinoline Alkaloid Analogues
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(Matrix Presented) A new one-step methodology has been introduced for the synthesis of quinoline alkaloid analogues. The reaction is based on a modification of the Mukaiyama aldol condensation, making use of the high reactivity of lactones or anhrydrides. The reaction is general and allows for the construction of new hetero polycondenced molecules in a one-step synthesis.
- Zografos, Alexandros L.,Mitsos, Christos A.,Igglessi-Markopoulou, Olga
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- Pd(ii)-Catalyzed [4 + 1 + 1] cycloaddition of simple: O -aminobenzoic acids, CO and amines: Direct and versatile synthesis of diverse N -substituted quinazoline-2,4(1 H,3 H)-diones
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The mild, efficient, and straightforward synthesis of pharmaceutically and biologically active N3-substituted and N1,N3-disubstituted quinazoline-2,4-(1H,3H)-diones from simple and readily available substrates has been a huge challenge. Described here is a Pd(ii)-catalyzed [4 + 1 + 1] modular synthesis of diverse quinazoline-2,4-(1H,3H)-diones through one-pot cascade reactions of cyclocondensation of o-(alkyl)aminobenzoic acids with CO, amidation of the intermediate isatoic anhydrides with amines, and unprecedented carbonylation of the resulting o-aminobenzamides with CO under 1 atm and 60 °C conditions. The chemoselective and versatile multicomponent reaction allows for the diversities of the products including N3-substituted and N1,N3-disubstituted products, and even makes the substituents on N1,N3 the same or different from each other, which cannot be achieved by most traditional synthetic strategies. This journal is
- Ding, Qianqian,Fan, Xuesen,Wang, Jinjun,Yang, Jingyi,Zhang, Guisheng,Zhang, Xiaopeng
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p. 526 - 535
(2021/01/28)
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- MODIFIED PROTEINS AND PROTEIN DEGRADERS
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Provided herein are compounds, pharmaceutical compositions, and methods for binding or degrading target proteins. Further provided herein are compounds having a DNA damage-binding protein 1 (DDB1) binding moiety. Some such embodiments include a linker. Some such embodiments include a target protein binding moiety. Further provided herein are ligand-DDB1 complexes. Further provided herein are in vivo modified DDB1 proteins.
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- Palladium-Catalyzed Multistep Tandem Carbonylation/N-Dealkylation/Carbonylation Reaction: Access to Isatoic Anhydrides
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A novel and efficient synthesis of isatoic anhydride derivatives was developed via palladium-catalyzed multistep tandem carbonylation/N-dealkylation/carbonylation reaction with alkyl as the leaving group and tertiary anilines as nitrogen nucleophiles. This approach features good functional group compatibility and readily available starting materials. Furthermore, it provided a convenient approach for the synthesis of biologically and medicinally useful evodiamine.
- Wang, Shoucai,Li, Xuan,Zang, Jiawang,Liu, Meichen,Zhang, Siyu,Jiang, Guangbin,Ji, Fanghua
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p. 2672 - 2679
(2020/02/04)
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- Synthesis and antibiofilm evaluation of 3-hydroxy-2,3-dihydroquinazolin-4(1H)-one derivatives against opportunistic pathogen Acinetobacter baumannii
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The emergence of multidrug resistant microorganisms has triggered the impending need for new aitimicrobial strategies. The antivirulence strategy with the benefite of alleviating the drug resistance becomes the focus of research. In this study, 22 quorum sensing inhibitors were synthesized by mimicking the structure of autoinducer and acinetobactin and up to 34% biofilm inhibition was observed with 5u. The biofilm inhibition effect was further demonstrated with extracellular polysaccharides inhibition and synergism with Gentamycin sulphate.
- Yang, Guo,Cheng, Cheng,Xu, Guo-Bo,Tang, Lei,Chua, Kim-Lee,Yang, Yuan-Yong
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- Benzoxazepine-Derived Selective, Orally Bioavailable Inhibitor of Human Acidic Mammalian Chitinase
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Human acidic mammalian chitinase (hAMCase) is one of two true chitinases in humans, the function of which remains elusive. In addition to the defense against highly antigenic chitin and chitin-containing pathogens in the gastric and intestinal contents, AMCase has been implicated in asthma, allergic inflammation, and ocular pathologies. Potent and selective small-molecule inhibitors of this enzyme have not been identified to date. Here we describe structural modifications of compound OAT-177, a previously developed inhibitor of mouse AMCase, leading to OAT-1441, which displays high activity and selectivity toward hAMCase. Significantly reduced off-target activity toward the human ether-à-go-go-related gene (hERG) and a good pharmacokinetic profile make OAT-1441 a potential candidate for further preclinical development as well as a useful tool compound to study the physiological role of hAMCase.
- Andryianau, Gleb,Bartoszewicz, Agnieszka,Czestkowski, Wojciech,Dymek, Barbara,Dzwonek, Karolina,Golab, Jakub,Golebiowski, Adam,Gruza, Mariusz,Koralewski, Robert,Kowalski, Michal,Matyszewski, Krzysztof,Mazur, Marzena,Niedziejko, Piotr,Olczak, Jacek,Olejniczak, Sylwia,Piotrowicz, Michal C.,Pluta, Elzbieta,Rajkiewicz, Adam A.,Rymaszewska, Aleksandra,Salamon, Magdalena,Sklepkiewicz, Piotr L.,Stefaniak, Filip,Welzer, Mikolaj,Zagozdzon, Agnieszka
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p. 1228 - 1235
(2020/07/03)
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- N-thiadiazole-4-hydroxy-2-quinolone-3-carboxamides bearing heteroaromatic rings as novel antibacterial agents: Design, synthesis, biological evaluation and target identification
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Due to the occurrence of antibiotic resistance, bacterial infectious diseases have become a serious threat to public health. To overcome antibiotic resistance, novel antibiotics are urgently needed. N-thiadiazole-4-hydroxy-2-quinolone-3-carboxamides are a potential new class of antibacterial agents, as one of its derivatives was identified as an antibacterial agent against S. aureus. However, no potency-directed structural optimization has been performed. In this study, we designed and synthesized 37 derivatives, and evaluated their antibacterial activity against S. aureus ATCC29213, which led to the identification of ten potent antibacterial agents with minimum inhibitory concentration (MIC) values below 1 μg/mL. Next, we performed bacterial growth inhibition assays against a panel of drug-resistant clinical isolates, including methicillin-resistant S. aureus, and cytotoxicity assays with HepG2 and HUVEC cells. One of the tested compounds named 1-ethyl-4-hydroxy-2-oxo-N-(5-(thiazol-2-yl)-1,3,4-thiadiazol-2-yl)-1,2-dihydroquinoline-3-carboxamide (g37) showed 2 to 128-times improvement compared with vancomycin in term of antibacterial potency against the tested strains (MICs: 0.25–1 μg/mL vs. 1–64 μg/mL) and an optimal selective toxicity (HepG2/MRSA, 110.6 to 221.2; HUVEC/MRSA, 77.6–155.2). Further, comprehensive evaluation indicated that g37 did not induce resistance development of MRSA over 20 passages, and it has been confirmed as a bactericidal, metabolically stable, orally active antibacterial agent. More importantly, we have identified the S. aureus DNA gyrase B as its potential target and proposed a potential binding mode by molecular docking. Taken together, the present work reports the most potent derivative of this chemical series (g37) and uncovers its potential target, which lays a solid foundation for further lead optimization facilitated by the structure-based drug design technique.
- Xue, Wenjie,Li, Xueyao,Ma, Guixing,Zhang, Hongmin,Chen, Ya,Kirchmair, Johannes,Xia, Jie,Wu, Song
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- Aza11-membered ring compound, preparation method and application thereof, and medicine containing aza11-membered ring compound
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The invention discloses an aza 11-membered ring compound haveing the following structural general formula shown in the specification, and also provides a method for preparing the compound. The methodcomprises the following steps of: under the condition of argon, by taking methylbenzene as a solvent, coordinating a tri(dibenzylidene acetone)dipalladium-chloroform adduct with a (4,5-bis(diphenylphosphine)-9,9-dimethylxanthene)phosphine ligand; stirring, adding a substrate 1 and a substrate 2 after the solution turns yellow from red, and carrying out a reaction to obtain a final product 3 afterthe reaction is finished. The invention also discloses application of the compound and a medicine containing the compound. According to the invention, the exploration of the compound with the middle ring structure is further deeply carried out, the compound with the middle ring structure also has pharmaceutical activity, the preparation method capable of expanding production and large-scale production is provided, the adopted reaction substrate raw materials are very easy to obtain, the reaction conditions of the preparation method are easy to realize, the reaction time is shortened to the maximum extent, and high yield can be obtained.
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Paragraph 0035; 0044-0047
(2021/01/15)
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- Carbene-Catalyzed Enantioselective Decarboxylative Annulations to Access Dihydrobenzoxazinones and Quinolones
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A direct decarboxylative strategy for the generation of aza-o-quinone methides (aza-o-QMs) by N-heterocyclic carbene (NHC) catalysis has been discovered and explored. This process requires no stoichiometric additives in contrast with current approaches. Aza-o-QMs react with trifluoromethyl ketones through a formal [4+2] manifold to access highly enantioenriched dihydrobenzoxazin-4-one products, which can be converted to dihydroquinolones through an interesting stereoretentive aza-Petasis–Ferrier rearrangement sequence. Complementary dispersion-corrected density functional theory (DFT) studies provided an accurate prediction of the reaction enantioselectivity and lend further insight to the origins of stereocontrol. Additionally, a computed potential energy surface around the major transition structure suggests a concerted asynchronous mechanism for the formal annulation.
- Lee, Ansoo,Zhu, Joshua L.,Feoktistova, Taisiia,Brueckner, Alexander C.,Cheong, Paul H.-Y.,Scheidt, Karl A.
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p. 5941 - 5945
(2019/04/03)
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- A method for utilizing the carbonylation reaction three-step synthetic evodiamine method (by machine translation)
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The invention discloses a three-step synthesis of carbonylation reaction evodiamine method. First of all in order to N, N - dimethyl aniline as the raw materials of reaction by oxidative carbonylation reaction to obtain N - methyl isatin anhydride, by ammonolysis reaction to obtain N - (2 - indole ethyl) - 2 - (methylamino) benzamide, finally through the cyclization reaction of the three-step synthesis tetradium alkalizing compound. The method of the invention the synthesis of novel means, reaction and is simple, the synthesis step is succinct, mild reaction conditions, the process is simple, consistent with the requirements of the development of green chemistry, and utilize the carbonylation reaction has succeeded in synthesizing evodiamine. (by machine translation)
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Paragraph 0013; 0019; 0028-0040
(2018/04/02)
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- Synthesis method of constructing isatoic anhydride and isatoic anhydride derivative by one step by utilizing carbonylation reaction
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The invention relates to a method of constructing isatoic anhydride and an isatoic anhydride derivative by one step by utilizing a carbonylation reaction. The method comprises the steps of adding N,N-dialkyl arylamine, a metal palladium catalyst and copper salt as an oxidant and a solvent to a reaction vessel, sleeving a balloon filled with carbon monoxide and oxygen on a reactor, performing a stirring reaction for 1-10h at 40-150 DEG C, performing cooling to a room temperature after reaction completion, dismounting the balloon, filtering a reaction liquid, performing reduced pressure evaporation to remove the solvent to obtain a crude product, and performing column chromatography purification to obtain isatoic anhydride and the isatoic anhydride derivative. The synthesis method of constructing isatoic anhydride and the isatoic anhydride derivative by the one step by utilizing the carbonylation reaction has the characteristics that operation is concise, raw materials are easy to obtain, the functional group tolerance is good, and a yield is excellent; and the method has an important research value on synthesis and preparation of isatoic anhydride and the isatoic anhydride derivative.
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Paragraph 0033-0062
(2017/11/16)
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- Palladium-Catalyzed Cyclization Reaction of o-Iodoanilines, CO2, and CO: Access to Isatoic Anhydrides
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Isatoic anhydrides, a class of valuable synthetic intermediates and RNA structure probing reagents, are usually prepared with highly toxic phosgene or stoichiometric oxidants. Herein we report a highly selective palladium-catalyzed cyclization reaction for the efficient synthesis of isatoic anhydrides from readily available o-iodoanilines, CO2, and CO. The reaction proceeds under mild conditions and is redox-neutral. Both CO2 and CO are indispensable C1 building blocks for this catalytic reaction.
- Zhang, Wen-Zhen,Zhang, Ning,Sun, Yu-Qian,Ding, Yu-Wei,Lu, Xiao-Bing
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p. 8072 - 8076
(2017/12/08)
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- Palladium-Catalyzed Ortho-Selective C-H Oxidative Carbonylation of N-Substituted Anilines with CO and Primary Amines for the Synthesis of o-Aminobenzamides
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An efficient, one-pot strategy with high selectivity and high atom economy for the synthesis of o-aminobenzamides has been developed via palladium-catalyzed ortho-selective C-H oxidative carbonylation of N-substituted anilines with CO and primary amines. A wide range of N-substituted anilines and primary amines can be tolerated in this transformation to afford the corresponding o-aminobenzamides in moderate to excellent yields under mild conditions.
- Zhang, Xiaopeng,Dong, Shuxiang,Niu, Xueli,Li, Zhengwei,Fan, Xuesen,Zhang, Guisheng
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supporting information
p. 4634 - 4637
(2016/09/28)
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- Investigation into the stability and reactivity of the pentacyclic alkaloid dehydroevodiamine and the benz-analog thereof
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Limited synthetic approaches to obtain the biologically active alkaloid dehydroevodiamine (DHED) are known to date. Undesired demethylation in the most widely applied route was found to be a hampering side reaction for the benz-DHED derivative leading to a quinazolinone, which represents a benz-rutaecarpine derivative. For rutaecarpine, a related plant alkaloid, many different synthetic approaches have been described. Alternative reaction procedures to obtain DHED such as methylation of rutaecarpine and oxidation of evodiamine were investigated to make DHED more easily accessible and the latter method proved to be the most successful one. Furthermore, the remarkable equilibrium between the ring closed quinazolinium and the ring open form of the compounds was systematically investigated by UV-vis measurements. The ring open form and the quinazolinium salt, form the same species when incubated in buffer solution for 24 h. A better soluble form, i.e., 'hydroxyevodiamine', seems to represent the biologically active form that has not yet been described.
- Wehle, Sarah,Espargaró, Alba,Sabaté, Raimon,Decker, Michael
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p. 2535 - 2543
(2016/04/26)
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- N-methyl isatin a process for the preparation of acid anhydride
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The invention provides a method for preparing N-methyl isatoic anhydride. The method comprises simple steps, is simple and convenient to operate, and is suitable for industrial production, and the raw materials are cheap and are easily available. The method comprises following steps of firstly taking anhydrous potassium carbonate as acid-binding agent and copper powder as a catalyst, carrying out a condensation reaction on o-chlorobenzoic acid and methylamine so as to obtain N-methyl o-aminobenzoic acid, and carrying out cyclization through condensation by adopting triphosgene and N-methyl o-aminobenzoic acid, so as to prepare the N-methyl isatoic anhydride.
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Paragraph 0010; 0030-0031
(2017/03/08)
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- Experimental and theoretical investigations into the stability of cyclic aminals
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Background: Cyclic aminals are core features of natural products, drug molecules and important synthetic intermediates. Despite their relevance, systematic investigations into their stability towards hydrolysis depending on the pH value are lacking. Results: A set of cyclic aminals was synthesized and their stability quantified by kinetic measurements. Steric and electronic effects were investigated by choosing appropriate groups. Both molecular mechanics (MM) and density functional theory (DFT) based studies were applied to support and explain the results obtained. Rapid decomposition is observed in acidic aqueous media for all cyclic aminals which occurs as a reversible reaction. Electronic effects do not seem relevant with regard to stability, but the magnitude of the conformational energy of the ring system and pKa values of the N-3 nitrogen atom. Conclusion: Cyclic aminals are stable compounds when not exposed to acidic media and their stability is mainly dependent on the conformational energy of the ring system. Therefore, for the preparation and work-up of these valuable synthetic intermediates and natural products, appropriate conditions have to be chosen and for application as drug molecules their sensitivity towards hydrolysis has to be taken into account.
- Sawatzky, Edgar,Drakopoulos, Antonios,R?lz, Martin,Sotriffer, Christoph,Engels, Bernd,Decker, Michael
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supporting information
p. 2280 - 2292
(2016/11/17)
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- Quinolinone compound and application thereof in drugs
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The invention relates to a quinolinone compound and application thereof in drugs, particularly relates to a novel quinolinone compound, a pharmaceutical composition thereof and use of the compound or the pharmaceutical composition in preparing drugs. The drug is used for protecting, disposing, treating or alleviating HIF-related and/or EPO-related diseases of patients, wherein the HIF-related and/or EPO-related diseases comprise anemia, vascular diseases, regional myocardial ischaemia, metabolic disturbance, wound healing and the like.
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Paragraph 0358; 0359; 0360; 0361; 0362
(2016/10/07)
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- Isatoic anhydride and its process for synthesis of derivatives of
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The invention discloses a synthesis method of isatoic anhydride and a derivative thereof, relating to the technical field of chemical synthesis. In the presence of catalysis of an organic selenium catalyst, isatin or a derivative thereof is oxidized by using hydrogen peroxide to prepare the isatoic anhydride and the derivative thereof. The synthesis method disclosed by the invention is simple and easily available in raw materials, low in cost, clean in oxidizing agent, free from a metal catalyst, and environmentally friendly, can be carried out in a neutral environment, and is small in corrosion to equipment.
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Paragraph 0048; 0049; 0050; 0051; 0052; 0053; 0054
(2017/01/12)
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- Palladium-catalyzed oxidative carbonylation of aromatic C-H bonds of N -alkylanilines with CO and alcohols for the synthesis of o -aminobenzoates
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A Pd(II)-catalyzed C-H monocarbonylation of N-alkylanilines for the synthesis of o-aminobenzoates has been developed. Various aliphatic alcohols and phenol were tolerated in the reaction to afford the corresponding o-aminobenzoates in good yields under mild balloon pressure of CO.
- Chen, Ming,Ren, Zhi-Hui,Wang, Yao-Yu,Guan, Zheng-Hui
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p. 1258 - 1263
(2015/01/30)
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- MIF INHIBITORS AND THEIR USES
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The invention relates to MIF inhibitors; compositions comprising an effective amount of a MIF inhibitor; and methods for treating or preventing diseases associated with MIF.
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Paragraph 1041
(2015/03/16)
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- Synthesis, biological evaluation and SAR of 3-benzoates of ingenol for treatment of actinic keratosis and non-melanoma skin cancer
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Ingenol 3-benzoates were investigated with respect to chemical stability, pro-inflammatory effects, cell death induction and PKCδ activation. A correlation between structure, chemical stability and biological activity was found and compared to ingenol mebutate (ingenol 3-angelate) used for field treatment of actinic keratosis. We also provided further support for involvement of PKCδ for induction of oxidative burst and cytokine release. Molecular modeling and dynamics calculations corroborated the essential interactions between key compounds and C1 domain of PKCδ.
- Grue-Sorensen, Gunnar,Liang, Xifu,Mansson, Kristoffer,Vedso, Per,Dahl Sorensen, Morten,Soor, Anke,Stahlhut, Martin,Bertelsen, Malene,Engell, Karen Margrethe,Hoegberg, Thomas
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- Metal-free oxidative synthesis of quinazolinones via dual amination of sp3 C-H bonds
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A novel metal-free synthesis of quinazolinones via dual amination of sp3 C-H bonds was developed. The sp3 carbon in methylarenes or adjacent to a heteroatom in DMSO, DMF or DMA was used as the one carbon synthon. This journal is the Partner Organisations 2014.
- Zhao, Dan,Wang, Teng,Li, Jian-Xin
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supporting information
p. 6471 - 6474
(2014/06/09)
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- A phosgene and peroxide-free one-pot tandem synthesis of isatoic anhydrides involving anthranilic acid, boc anhydride and 2-chloro-N-methyl pyridinium iodide
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A phosgene and peroxide-free approach for the synthesis of isatoic anhydrides has been described. The synthesis involves the carbamate formation with boc anhydride followed by in situ cyclization to afford the isatoic anhydride. The importance of this synthetic strategy is in the ease of operation, scalability and preparation from readily available raw materials.
- Verma, Chhaya,Sharma, Somesh,Pathak, Arunendra
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supporting information
p. 6897 - 6899
(2019/04/10)
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- Palladium-catalyzed regioselective carbonylation of C-H bonds of N -alkyl anilines for synthesis of isatoic anhydrides
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A Pd-catalyzed regioselective C-H bond carbonylation of N-alkyl anilines for the synthesis of isatoic anhydrides has been developed. The key Pd-catalyst intermediate has been isolated and characterized. This novel Pd-catalyzed carbonylation reaction tolerates a wide range of functional groups and is a reliable method for the rapid elaboration of readily available N-alkyl anilines into a variety of substituted isatoic anhydrides under mild conditions.
- Guan, Zheng-Hui,Chen, Ming,Ren, Zhi-Hui
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supporting information
p. 17490 - 17493,4
(2020/09/16)
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- New tricks for an Old natural product: Discovery of highly potent evodiamine derivatives as novel antitumor agents by systemic structure-activity relationship analysis and biological evaluations
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Evodiamine is a quinazolinocarboline alkaloid isolated from the fruits of traditional Chinese herb Evodiae fructus. Previously, we identified N13-substituted evodiamine derivatives as potent topoisomerase I inhibitors by structure-based virtual screening and lead optimization. Herein, a library of novel evodiamine derivatives bearing various substitutions or modified scaffold were synthesized. Among them, a number of evodiamine derivatives showed substantial increase of the antitumor activity, with GI50 values lower than 3 nM. Moreover, these highly potent compounds can effectively induce the apoptosis of A549 cells. Interestingly, further computational target prediction calculations in combination with biological assays confirmed that the evodiamine derivatives acted by dual inhibition of topoisomerases I and II. Moreover, several hydroxyl derivatives, such as 10-hydroxyl evodiamine (10j) and 3-amino-10-hydroxyl evodiamine (18g), also showed good in vivo antitumor efficacy and low toxicity at the dose of 1 mg/kg or 2 mg/kg. They represent promising candidates for the development of novel antitumor agents.
- Dong, Guoqiang,Wang, Shengzheng,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Yongqiang,Guo, Zizhao,Zhang, Wannian,Sheng, Chunquan
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p. 7593 - 7613
(2012/10/29)
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- Neuroprotective tri- and tetracyclic BChE inhibitors releasing reversible inhibitors upon carbamate transfer
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Tri- and tetracyclic nitrogen-bridgehead compounds were designed and synthesized to yield micromolar cholinesterase (ChE) inhibitors. Structure-activity relationships identified potent compounds with butyrylcholinesterase selectivity. These compounds were selected as starting points for the design and synthesis of carbamate-based (pseudo)irreversible inhibitors. Compounds with superior inhibitory activity and selectivity were obtained and kinetically characterized also with regard to the velocity of enzyme carbamoylation. Structural elements were identified and introduced that additionally showed neuroprotective properties on a hippocampal neuronal cell line (HT-22) after glutamate-induced intracellular reactive oxygen species generation. We have identified potent and selective pseudoirreversible butyrylcholinesterase inhibitors that release reversible inhibitors with neuroprotective properties after carbamate transfer to the active site of cholinesterases.
- Darras, Fouad H.,Kling, Beata,Heilmann, J?rg,Decker, Michael
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p. 914 - 919
(2013/01/15)
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- HIGHLY PURE LAQUINIMOD OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
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Provided herein is an impurity of laquinimod, N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxamide (deschloro laquinimod impurity), and process for preparation and isolation thereof. Provided further herein is a highly pure laquinimod or a pharmaceutically acceptable salt thereof substantially free of deschloro laquinimod impurity, processes for the preparation thereof, and pharmaceutical compositions comprising highly pure laquinimod or a pharmaceutically acceptable salt thereof substantially free of deschloro laquinimod impurity.
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Page/Page column 3; 11
(2012/01/15)
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- 3-ACYL-INGENOLS II
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The invention relates to compounds of general formula I, (I), wherein R is wherein R is aryl substituted by R3; or R is (C3-Ci3)-cycloalkyl, (C3-Ci3)- cycloalkenyl or (C7-Ci3)-cycloalkynyl optionally substituted by R4; and pharmaceutically acceptable salts, hydrates, or solvates thereof, for use -alone or in combination with one or more other pharmaceutically active compounds- in therapy, for preventing, treating or ameliorating diseases or conditions responsive to stimulation of neutrophil oxidative burst, responsive to stimulation of keratinocyte IL-8 release or responsive to induction of necrosis.
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Page/Page column 42
(2012/07/13)
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- MIF INHIBITORS AND THEIR USES
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The invention relates to MIF inhibitors; compositions comprising an effective amount of a MIF inhibitor; and methods for treating or preventing diseases associated with MIF.
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Page/Page column 90
(2012/02/02)
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- Synthesis, biological assessment and molecular modeling of new dihydroquinoline-3-carboxamides and dihydroquinoline-3-carbohydrazide derivatives as cholinesterase inhibitors, and Ca channel antagonists
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The synthesis, biological evaluation, and molecular modeling of new 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides(4), 4-hydroxy-2-oxo-1,2- dihydroquinoline-3-carbohydrazide (6), and some hexahydropyrimido[5,4-c] quinoline-2,5-diones (9) produced earlier by our laboratory, as AChE/BuChE inhibitors, is described. From these analyses compound 4c resulted equipotent regarding the inhibition of cholinesterases'; inhibitors 6k, 9a, 9b were selective for AChE, whereas product 4d proved selective for BuChE. Docking analysis has been carry out in order to identify the binding mode in the active site, and to explain the observed selectivities. Only compound 9a has been shown to decrease K+-induced calcium signals in bovine chromaffin cells.
- Tomassoli, Isabelle,Ismaili, Lhassane,Pudlo, Marc,De Los Ríos, Cristóbal,Soriano, Elena,Colmena, Inés,Gandía, Luis,Rivas, Luis,Samadi, Abdelouahid,Marco-Contelles, José,Refouvelet, Bernard
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scheme or table
p. 1 - 10
(2011/02/27)
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- 1,3-dipolar cycloaddition-decarboxylation reactions of an azomethine ylide with isatoic anhydrides: Formation of novel benzodiazepinones
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A nonstabilized azomethine ylide reacts with a wide range of substituted isatoic anhydrides to afford novel 1,3-benzodiazepin-5-one derivatives, which are generally isolated in high yield. The transformations involve 1,3-dipolar cycloaddition reactions of the ylide with the anhydrides to give transient, and in a representative case spectroscopically observable, oxazolidine intermediates that undergo ring-opening-decarboxylation-ringclosing reaction cascades to yield the 1,3-benzodiazepin-5-one products.
- D'Souza, Asha M.,Spiccia, Nadia,Basutto, Jose,Jokisz, Pawel,Wong, Leon S.-M.,Meyer, Adam G.,Holmes, Andrew B.,White, Jonathan M.,Ryan, John H.
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supporting information; experimental part
p. 486 - 489
(2011/03/23)
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- COMPOUNDS THAT MODULATE EGFR ACTIVITY AND METHODS FOR TREATING OR PREVENTING CONDITIONS THEREWITH
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Provided are compounds and methods for treating or preventing kinase-mediated disorders therewith.
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Page/Page column 85-86
(2011/11/30)
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- Intramolecular N-aza-amidoalkylation in association with Witkop-Winterfeldt oxidation as the key step to synthesize Luotonin-A analogues
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An expedient four-step approach for the synthesis of a short library of original analogues of the Topo-I Luotonin-A inhibitor, substituted at their C8- and N15-positions, was investigated. This consists of Rutaecarpines formation, their Witkop-Winterfeldt oxidation followed ultimately with functional adjustment of the pyrroloquinolone intermediates. In the first step of these investigations, Rutaecarpines including the Topo-I poison Evodiamine were obtained via the new tandem N-acylation/aza-amidoalkylation using a nitrogen atom as an internal nucleophile with or without association with a decarboxylation.
- Pin, Frédéric,Comesse, Sébastien,Da?ch, Adam
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scheme or table
p. 5564 - 5571
(2011/08/09)
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- HIGHLY PURE LAQUINIMOD OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
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Provided herein is an impurity of laquinimod, N-ethyl-N-phenyl-1,2-dihydro-4-hydroxy-1- methyl-2-oxoquinoline-3-carboxamide (deschloro laquinimod impurity), and process for preparation and isolation thereof. Provided further herein is a highly pure laquinimod or a pharmaceutically acceptable salt thereof substantially free of deschloro laquinimod impurity, processes for the preparation thereof, and pharmaceutical compositions comprising highly pure laquinimod or a pharmaceutically acceptable salt thereof substantially free of deschloro laquinimod impurity.
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Page/Page column 26
(2010/08/05)
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- Selection of evodiamine as a novel topoisomerase i inhibitor by structure-based virtual screening and hit optimization of evodiamine derivatives as antitumor agents
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Human topoisomerase I (TopoI) is recognized as a valuable target for the development of effective antitumor agents. Structure-based virtual screening was applied to the discovery of structurally diverse TopoI inhibitors. From 23 compounds selected by virtual screening, a total of 14 compounds were found to be TopoI inhibitors. Five hits (compounds 1, 14, 20, 21, and 23) also showed moderate to good in vitro antitumor activity. These novel structures can be considered as good starting points for the development of new antitumor lead compounds. Hit 20 (evodiamine) was chosen for preliminary structure-activity relationship studies. Various groups, including alkyl, benzoyl, benzyl and ester, were introduced to the indole nitrogen atom of evodiamine. The substituted benzoyl groups were found to be favorable for the antitumor activity and spectrum. The 4-Cl benzoyl derivative, compound 29u, was the most active one with IC50 values in the range 0.049-2.6 μM.
- Dong, Guoqiang,Sheng, Chunquan,Wang, Shengzheng,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian
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scheme or table
p. 7521 - 7531
(2011/02/21)
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- Photolysis of indan-l,2-dione derivatives in oxygen-doped argon matrix at low temperature
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Photolysis of indan-l,2,3-trion (la), benzo[ft]furan-2,3-dione (lb), and N-methylisatin (1c) in argon matrix either with or without oxygen at 10 K was investigated by IR spectroscopy in combination with DFT calculations. The results indicate that while 1a and 1b gave the products mixture as a result of α-cleavage, followed by decarbonylation, 1c was rather photostable under similar conditions. However, when the irradiation was carried out in argon matrix doped with 20% oxygen, 1c decomposed much more efficiently than that in argon matrix and cyclic diacyl peroxide presumably formed by trapping of initial diradical originating from α-cleavage by molecular oxygen was detected. Similar irradiation of 1b also gave cyclic diacyl peroxide along with photodecarbonylation products, but irradiation of 1a in oxygen-doped matrix produced not only cyclic diacyl peroxide but also products as a result of oxidation of photodecarbonylation product. The present observation reveals that photolysis of ketones in oxygen-doped matrix at low temperature provides useful information concerning the reactivities of ketones toward α-cleavage.
- Itoh, Takayoshi,Tatsugi, Jiro,Tomioka, Hideo
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body text
p. 475 - 481
(2009/08/07)
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- A practical method for preparation of 4-hydroxyquinolinone esters
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(Chemical Equation Presented) 4-Hydroxyquinolinone esters are a common motif for many medicinal agents. Several methods exist for preparation of these compounds, generally involving the use of sodium hydride, which raises significant safety issues and limits their application to large-scale synthesis. In this note a practical, safe, and general method that employs a combination of diisopropylethylamine and sodium tert-butoxide is described. This allows for the synthesis of 4-hydroxyquinolinone esters and amides in good yields.
- Beutner, Gregory L.,Kuethe, Jeffrey T.,Yasuda, Nobuyoshi
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p. 7058 - 7061
(2008/02/11)
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- 3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones, potent inhibitors of hepatitis C virus RNA-dependent RNA polymerase
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Recently, we disclosed a new class of HCV polymerase inhibitors discovered through high-throughput screening (HTS) of the GlaxoSmithKline proprietary compound collection. This interesting class of 3-(1,1-dioxo-2H-1,2,4- benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones potently inhibits HCV polymerase enzymatic activity and inhibits the ability of the subgenomic HCV replicon to replicate in Huh-7 cells. This report will focus on the structure-activity relationships (SAR) of substituents on the quinolinone ring, culminating in the discovery of 1-(2-cyclopropylethyl)-3-(1,1-dioxo-2H-1,2,4- benzothiadiazin-3-yl)-6-fluoro-4-hydroxy-2(1H)-quinolinone (130), an inhibitor with excellent potency in biochemical and cellular assays possessing attractive molecular properties for advancement as a clinical candidate. The potential for development and safety assessment profile of compound 130 will also be discussed.
- Tedesco, Rosanna,Shaw, Antony N.,Bambal, Ramesh,Chai, Deping,Concha, Nestor O.,Darcy, Michael G.,Dhanak, Dashyant,Fitch, Duke M.,Gates, Adam,Gerhardt, Warren G.,Halegoua, Dina L.,Han, Chao,Hofmann, Glenn A.,Johnston, Victor K.,Kaura, Arun C.,Liu, Nannan,Keenan, Richard M.,Lin-Goerke, Juili,Sarisky, Robert T.,Wiggall, Kenneth J.,Zimmerman, Michael N.,Duffy, Kevin J.
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p. 971 - 983
(2007/10/03)
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- Synthesis and Biological Evaluation of New 1,2-Dihydro-4-hydroxy-2-oxo-3-quinolinecarboxamides for Treatment of Autoimmune Disorders: Structure-Activity Relationship
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Roquinimex-related 3-quinolinecarboxamide derivatives were prepared and evaluated for treatment of autoimmune disorders. The compounds were tested in mice for their inhibitory effects on disease development in the acute experimental autoimmune encephalomyelitis model and selected compounds in the beagle dog for induction of proinflammatory reaction. Structure-activity relationships are discussed. Compound 8c, laquinimod, showed improved potency and superior toxicological profile compared to the lead compound roquinimex (1b, Linomide) and was selected for clinical studies (currently in phase II).
- J?nsson, Stig,Andersson, Gunnar,Fex, Tomas,Fristedt, Tomas,Hedlund, Gunnar,Jansson, Karl,Abramo, Lisbeth,Fritzson, Ingela,Pekarski, Olga,Runstr?m, Anna,Sandin, Helena,Thuvesson, Ingela,Bj?rk, Anders
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p. 2075 - 2088
(2007/10/03)
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- MUSCARINIC ANTAGONISTS
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Amide derivatives of 1,4 di-substituted piperidine compounds of formula (I) or a pharmaceutically acceptable salt, ester or solvate thereof, wherein Q and Q are each -CH=, or one of Q and Q is -CH= and the other is -N=; X is -CH2- or (a); Y and Z are -C(R)=, or one of Y and Z is -C(R)= and the other is -N=; R is 1 to 3 substituents selected from H, halogen and alkoxy; R and R are 1 to 3 substituents selected from H, halogen, alkyl and alkoxy; and R and R are H or (C1-C6) alkyl are muscarinic antagonists usuful for treating cognitive disorders such as Alzheimer's disease. Pharmaceutical compositions and methods of preparation are also disclosed.
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- Synthesis of 2-aminoquinazoline-4(3H)-one derivatives as potential potassium channel openers
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Starting from 2-thioxoquinazolin-4-one, the synthesis of 2-amino-4(3H)- one derivatives, structurally related to potassium channels openers pinacidil and diazoxide, is described.
- Erb, Benedicte,Akue, Rufine,Rigo, Benoit,Pirotte, Bernard,Couturier, Daniel
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p. 253 - 260
(2007/10/03)
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- Studies of Rutaecarpine and Related Quinazolinocarboline Alkaloids
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Quinazolinocarboline alkaloids, e.g., rutaecarpine (1), can readily be synthesized by treating tryptamine with 2-(trifluoromethyl)-4H-3,1-benzoxazin-4-one (quickly generated in situ from trifluoroacetic anhydride (TFAA) and 2H-3,1-benzoxazine-2,4(1H)-dione.The product formed, 3--2-(trifluoromethyl)-4-(3H)-quinazolinone (5), is then cyclized (HCl/HOAc) to 13b-(trifluoromethyl)-13b,14-dihydrorutaecarpine (6), whereupon CF3H is eliminated by treatment with base.The sequence can conveniently be performed as a three-reaction one-pot procedure giving rutaecarpine (1) in 99percent yield within 3h.The approach can readily be extended to the synthesis of evodiamine (2), 13,13b-dehydroevodiamine (38a), and 13b,14-dihydrorutaecarpine (21).Thus treatment of 3--4(3H)-quinazolinone (19) with TFAA affected cyclization to 13b-(trifluoroacetyl)-13b,14-dihydrorutaecarpine (20), which can be readily hydrolyzed to 13b,14-dihydrorutaecarpine (21).
- Bergman, Jan,Bergman, Solveig
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p. 1246 - 1255
(2007/10/02)
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