- Synthesis of the pentacyclic core of lihouidine
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The pentacyclic base of the sponge-derived alkaloid lihouidine has been assembled from two quinoline fragments. The key step is a nitration-promoted cyclization to form the C-C bond between the two quinoline units.
- Feldman, Ken S.,Coca, Adiel
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- Synthesis, crystal structure, spectroscopic characterization, Hirshfeld surface analysis, molecular docking studies and DFT calculations, and antioxidant activity of 2-oxo-1,2-dihydroquinoline-4-carboxylate derivatives
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A series of hydroquinolines derivatives (2a-2c) have been achieved by a cyclocondensation reaction. The synthesis of 2-oxo ?1,2-dihydroquinoline-4-carboxylic acid derivatives (3a-3c) has been carried out using alkylation reactions under phase transfer catalysis (PTC) conditions. The prepared products were characterized through spectroscopic NMR 1H and 13C, IR and single crystal X-ray diffraction techniques. 2D and 3D Hirshfeld surfaces (for 3a and 3b) studies were realized to understand non-bonding intermolecular interactions in solid phase crystal packing of the compound. With the optimized structures, the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) energies and clouds were obtained and evaluated. Good agreement was found between the calculated results and experimental data. Furthermore, the molecular docking study is performed to investigate binding patterns of the synthesized molecules (3a and 3b) into 1M17 inhibitor using Auto-Dock Vina program. The antioxidant activity of compounds (3a-3c) has been evaluated using DPPH free radical scavenging, ferric reducing (FRAP) power and β-carotene kinetic blanching assays. Both DPPH and FRAP methods confirmed that 3b had the best antioxidant activity followed by 3c. On the other hand, β-carotene bleaching assay showed the high activity of the product 3a.
- Filali Baba, Yassir,Sert, Yusuf,Kandri Rodi, Youssef,Hayani, Sonia,Mague, Joel T.,Prim, Damien,Marrot, Jerome,Ouazzani Chahdi, Fouad,Sebbar, Nada Kheira,Essassi, El Mokhtar
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- Discovery, synthesis and molecular substantiation of N-(benzo[d]thiazol-2-yl)-2-hydroxyquinoline-4-carboxamides as anticancer agents
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The effort was taken to develop a series of benzothiazole and quinoline fused bioactive compounds obtained through a four-step synthetic route using a range of substituted acetoacetanilides. Achieved N-(benzo[d]thiazol-2-yl)-2-hydroxyquinoline-4-carboxamides (6a-l) were produced up to 96% of yield while the eco-friendly p-TSA used as a catalyst. Further, the anticancer activity of these compounds was determined using a range of cancer cell lines starting from MCF-7 (Breast cancer), HCT-116 (Colon cancer), PC-3 & LNCaP (Prostate) and SK-HEP-1 (Liver cancer). Present study compounds were also testified for antioxidant properties prior to anticancer studies since the Reactive Oxygen Species (ROS) being vital in cancer development. To determine the cell membrane stability effects of the compounds, human red blood cells (HRBC) based membrane protection assay was determined. In the results, compounds 6a-l were able to produce a dominated result values over PC3 cell lines (Prostate cancer) than the other cell lines used in this study. Since the connectivity of human germ cell alkaline phosphatase (hGC-ALP) in the development of prostate cancer is known, the most active compounds were evaluated for the hGC-ALP inhibition in order to ensure a mechanism of anticancer action of these compounds. The mode of interaction and binding affinity of these compounds was also investigated by a molecular docking study. In the results, 6d, 6i, 6k, and 6l were found with least IC50 values 0.075 μM and highest relative activity of 92%, 90%, and 96% respectively. The need for further animal model evaluation and pre-clinical studies recognized.
- Bindu,Vijayalakshmi,Manikandan
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- Identification of the characteristic components in walnut and anti-inflammatory effect of glansreginin A as an indicator for quality evaluation
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Walnut is a nutritious food material, but only a few studies have been conducted on the mechanisms of its functions and the technique for quality evaluation. Therefore, we analyzed the components in aqueous methanol extract of walnut, and characterized 30 components, including three new compounds, glansreginin C, ellagic acid 4-O-(3′-O-galloyl)-β-D-xyloside, and platycaryanin A methyl ester. We analyzed the extracts of other nuts using HPLC and clarified that a characteristic peak corresponding to glansreginin A was mainly observed in walnut. These results suggested that glansreginin A might be an indicator component of the quality of walnut. We then examined whether glansreginin A has neuroprotective effect, using lipopolysaccharide (LPS)-induced inflammatory model mice. The results revealed that oral administration of glansreginin A prevented LPS-induced abnormal behavior and LPS-induced hyper-activation of microglia in the hippocampus. These results suggested that glansreginin A has the ability to exert neuroprotective effect via anti-inflammation in the brain.
- Haramiishi, Rie,Okuyama, Satoshi,Yoshimura, Morio,Nakajima, Mitsunari,Furukawa, Yoshiko,Ito, Hideyuki,Amakura, Yoshiaki
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- Design, synthesis and evaluation of a new calix[4]arene based molecular receptor for multiple ion selectivity
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The hydrophobic and conformational motifs of calix[4]arene stereostructure and plausible binding characteristics of heterocyclic 2-oxo-1,2-dihydroquinoline-4-carbohydrazide have been deployed for the design and synthesis of a new molecular receptor, 4 for multi-ion recognition. The target molecule was synthesized through the condensation of 3 with 2-oxo-1,2-dihydroquinoline-4-carbohydrazide (6) in refluxing ethanol. It has been determined that 4 exhibits an exclusive color change from colorless to yellow as well as a 5.5 fold increase in the fluorescence intensity upon interaction with fluoride due to formation of multiple hydrogen bonds. Consequent to fluoride induced deprotonation, 4 displays a dual selectivity for Cu2+ and Ni2+ ions from amongst plethora of investigated cations.
- Chawla, Har Mohindra,Gupta, Tanu
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- Discovery of Novel Quinoline-Chalcone Derivatives as Potent Antitumor Agents with Microtubule Polymerization Inhibitory Activity
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A series of novel quinoline-chalcone derivatives were designed, synthesized, and evaluated for their antiproliferative activity. Among them, compound 24d exhibited the most potent activity with IC50 values ranging from 0.009 to 0.016 μM in a panel of cancer cell lines. Compound 24d also displayed a good safety profile with an LD50 value of 665.62 mg/kg by intravenous injection, and its hydrochloride salt 24d-HCl significantly inhibited tumor growth in H22 xenograft models without observable toxic effects, which was more potent than that of CA-4. Mechanism studies demonstrated that 24d bound to the colchicine site of tubulin, arrested the cell cycle at the G2/M phase, induced apoptosis, depolarized mitochondria, and induced reactive oxidative stress generation in K562 cells. Moreover, 24d has potent in vitro antimetastasis and in vitro and in vivo antivascular activities. Collectively, our findings suggest that 24d deserves to be further investigated as a potent and safe antitumor agent for cancer therapy.
- Li, Wenlong,Xu, Feijie,Shuai, Wen,Sun, Honghao,Yao, Hong,Ma, Cong,Xu, Shengtao,Yao, Hequan,Zhu, Zheying,Yang, Dong-Hua,Chen, Zhe-Sheng,Xu, Jinyi
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- Quinoline carboxamide core moiety-based compounds inhibit P. falciparum falcipain-2: Design, synthesis and antimalarial efficacy studies
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Targeting Falcipain-2 (FP2) for the development of antimalarials is a promising and established concept in antimalarial drug discovery and development. FP2, a member of papain-family cysteine protease of the malaria parasite Plasmodium falciparum holds an important role in hemoglobin degradation pathway. A new series of quinoline carboxamide-based compounds was designed, synthesized and evaluated for antimalarial activity. We integrated molecular hybridization strategy with in-silico drug design to develop FP2 inhibitors. In-vitro results of FP2 inhibition by Qs17, Qs18, Qs20 and Qs21 were found to be in low micromolar range with IC50 4.78, 7.37, 2.14 and 2.64 μM, respectively. Among the 25 synthesized compounds, four compounds showed significant antimalarial activities. These compounds also depicted morphological and food-vacuole abnormalities much better than that of E-64, an established FP2 inhibitor. Overall these aromatic substituted quinoline carboxamides can serve as promising leads for the development of novel antimalarial agents.
- Singh, Anju,Kalamuddin, Md,Maqbool, Mudasir,Mohmmed, Asif,Malhotra, Pawan,Hoda, Nasimul
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- Syntheses of novel 2-oxo-1,2-dihydroquinoline derivatives: Molecular and crystal structures, spectroscopic characterizations, Hirshfeld surface analyses, molecular docking studies and density functional theory calculations
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Sixteen new quinoline derivatives (3–18) have been synthesized through cyclocondensation, nucleophilic substitution and alkylation reactions. All the obtained compounds have been characterized using 1H-, 13C and 19F NMR spectroscopic measurements. The molecular and crystal structures of four of these compounds (10, 11, 15 and 18) have also been further examined by single crystal X-ray crystallography. The predicted spectral data were also obtained and compared to the experimental results using density functional theory (DFT). in order to understand the non-bonding intermolecular interactions in solid phase crystal packing. The closest contacts between active atoms of the four studied molecules were identified through both 2D and 3D Hirshfeld surface analyses. The different structures of the four compounds are optimized and their both energies highest occupied molecular orbitals (HOMO) and lowest unoccupied molecular orbitals (LUMO), as well as their clouds are evaluated. The obtained experimental results are correlated to the calculated ones and showed great compatibility. Finally, molecular docking studies are performed to investigate the binding patterns of the title compounds with the Protein Data Bank (PDB: 1M17) inhibitor targets and showed good insights on the possible interactions using the Auto-Dock Vina program.
- Baba, Yassir Filali,Boukir, Abdellatif,Chahdi, Fouad Ouazzani,Essassi, El Mokhtar,G?kce, Halil,H?kelek, Tuncer,Hayani, Sonia,Jasinski, Jerry P.,Kaur, Manpreet,Rodi, Youssef Kandri,Sebbar, Nada Kheira
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- Quinoline substituted chalcone compound as well as preparation method and application thereof
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The invention discloses a novel quinoline substituted chalcone compound as well as pharmaceutically acceptable salts and a preparation method thereof. The invention further discloses a pharmaceuticalcomposition which comprises a therapeutically effective amount of the novel quinoline substituted chalcone compound and/or the pharmaceutically acceptable salts and a pharmaceutically acceptable carrier. The invention further discloses a tubulin inhibitor which comprises the novel quinoline substituted chalcone compound and/or the pharmaceutically acceptable salts. The invention further disclosesapplication of the novel quinoline substituted chalcone compound and/or the pharmaceutically acceptable salts in preparing drugs for treating but not limited to colon cancer, leukemia, liver cancer, breast cancer and other diseases. The compound in the application shows excellent anti-tumor activity, and has more stable metabolic properties and better druggability prospect.
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Paragraph 0027; 0100; 0102; 0103
(2019/03/29)
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- Inhibition of: O -GlcNAc transferase (OGT) by peptidic hybrids
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O-GlcNAc transferase (OGT) attaches a GlcNAc moiety on specific substrate proteins using UDP-GlcNAc as the sugar donor. This modification can alter protein function by regulating cellular signaling and transcription pathways in response to altered nutrient availability and stress. Specific inhibitors of OGT would be valuable tools for biological studies and lead structures for therapeutics. The existing OGT inhibitors are mainly derived from the sugar donor substrate, but poor cell permeability and off-target effects limit their use. Here, we describe our progress on OGT inhibition based on substrate peptides identified by array screening. Subsequently, bisubstrate inhibitors were prepared by conjugating these peptides to uridine in various ways. In parallel, an in silico fragment screening was conducted to obtain small molecules targeting the UDP binding pocket. After evaluation of the initial hits, one of these small molecules was elaborated into a novel OGT hybrid inhibitor, as the replacement of uridine. The novel compounds inhibit OGT activity with IC50 values in the micromolar range.
- Zhang, Hao,Toma?i?, Tihomir,Shi, Jie,Weiss, Matjaz,Ruijtenbeek, Rob,Anderluh, Marko,Pieters, Roland J.
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supporting information
p. 883 - 887
(2018/05/31)
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- Preparation method of 2-hydroxy-4-carboxylquinoline
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The invention belongs to the technical field of chemical synthesis and in particular relates to a production preparation method of a dibucaine hydrochloride intermediate 2-hydroxy-4-carboxylquinoline.The method comprises the following steps: (1) putting glacial acetic acid into a reaction kettle; while stirring, adding isatin, malonic acid and sodium acetate; (2) heating the solution in step (1)and raising the temperature until the solution is reflowed; after reflowing, cooling to room temperature; (3) decompressing and evaporating materials in step (2) to remove the glacial acetic acid (which is recycled); (4) adding de-ionized water into the materials which are subjected to evaporation to remove the glacial acetic acid in step (3), and stirring and crystallizing; after finishing crystallization, spinning and filtering; eluting with the glacial acetic acid and then eluting with methanol; drying a wet product to obtain the 2-hydroxy-4-carboxylquinoline. The synthesis method providedby the invention adopts a one-spoon stewing technology to obtain a target product, so that the operation is simplified, the production period is shortened and the production cost is reduced; the obtained product has high purity and high yield and is suitable for large-scale production.
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Paragraph 0021; 0023
(2018/06/26)
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- Oxidative Reactivities of 2-Furylquinolines: Ubiquitous Scaffolds in Common High-Throughput Screening Libraries
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High-throughput screening (HTS) was employed to discover APOBEC3G inhibitors, and multiple 2-furylquinolines (e.g., 1) were found. Dose-response assays with 1 from the HTS sample, as well as commercial material, yielded similar confirmatory results. Interestingly, freshly synthesized and DMSO-solubilized 1 was inactive. Repeated screening of the DMSO aliquot of synthesized 1 revealed increasing APOBEC3G inhibitory activity with age, suggesting that 1 decomposes into an active inhibitor. Laboratory aging of 1 followed by analysis revealed that 1 undergoes oxidative decomposition in air, resulting from a [4 + 2] cycloaddition between the furan of 1 and 1O2. The resulting endoperoxide then undergoes additional transformations, highlighted by Baeyer-Villager rearrangements, to deliver lactam, carboxylic acid, and aldehyde products. The endoperoxide also undergoes hydrolytic opening followed by further transformations to a bis-enone. Eight structurally related analogues from HTS libraries were similarly reactive. This study constitutes a cautionary tale to validate 2-furylquinolines for structure and stability prior to chemical optimization campaigns.
- Olson, Margaret E.,Abate-Pella, Daniel,Perkins, Angela L.,Li, Ming,Carpenter, Michael A.,Rathore, Anurag,Harris, Reuben S.,Harki, Daniel A.
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supporting information
p. 7419 - 7430
(2015/10/05)
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- Anti-Malarial Agents
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The present invention relates to a novel class of quinolone-4-carboxamide Pf3D7 inhibitors of general formula (I) (Formula (I)) wherein R1, R2, R3, R4, R5, R6, R7, R8 and X are as defined herein, to their use in medicine, and in the treatment of malaria in particular, to compositions containing them, to processes for their preparation and to intermediates used in such processes.
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Paragraph 0271-0274
(2015/02/25)
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- ANTI-MALARIAL AGENTS
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The present invention relates to a novel class of quinolone-4-carboxamide Pf3D7 inhibitors of general formula (I) (Formula (I)) wherein R1, R2, R3, R4, R5, R6, R7, R8 and X are as defined herein, to their use in medicine, and in the treatment of malaria in particular, to compositions containing them, to processes for their preparation and to intermediates used in such processes.
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Page/Page column 44
(2013/11/05)
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- Construction and functionalization of fused pyridine ring leading to novel compounds as potential antitubercular agents
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A series of fused and functionalized pyridine derivatives were designed, synthesized and tested for their potential antitubercular properties. All these novel compounds were prepared by using multistep methods involving the construction of pyridine ring as a key synthetic step. Some of these compounds were found to be interesting when tested for their antitubercular properties in vitro and one of them appeared as an attractive and potential antitubercular agent.
- Dulla, Balakrishna,Wan, Baojie,Franzblau, Scott G.,Kapavarapu, Ravikumar,Reiser, Oliver,Iqbal, Javed,Pal, Manojit
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supporting information; experimental part
p. 4629 - 4635
(2012/07/31)
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- Synthesis and anti-tuberculosis activity of 2,4-disubstituted quinolines
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Synthesis and anti-tuberculosis activity of a new series of 2,4-disubstituted quinolines have been reported. The most promising compounds have been found to exhibit 99% inhibition at 6.25 ng/mL against drug-sensitive M. tuberculosis H37Rv strain and >90% inhibition at 12.5 ng/mL against isoniazid resistant TB strain.
- Nayyar, Amit,Jain, Rahul
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p. 117 - 128
(2008/09/20)
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- Two novel dicarboxylic acid derivatives and a new dimeric hydrolyzable tannin from walnuts
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In addition to the 16 previously reported polyphenols including 3 new ellagitannins, 2 novel dicarboxylic acid derivatives, glansreginins A (1) and B (2), and a new dimeric hydrolyzable tannin, glansrin D (3), were isolated, together with 15 known compounds from walnuts, the seeds of Juglans regia. The structures of the new compounds were elucidated on the basis of 1D- and 2D-NMR analyses and chemical data. The antioxidant effect of these isolates was also evaluated by SOD-like and DPPH radical scavenging activities.
- Ito, Hideyuki,Okuda, Takahiro,Fukuda, Toshiyuki,Hatano, Tsutomu,Yoshida, Takashi
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experimental part
p. 672 - 679
(2009/09/30)
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- Further studies on the interaction of the 5-hydroxytryptamine3 (5-HT3) receptor with arylpiperazine ligands. Development of a new 5-HT3 receptor ligand showing potent acetylcholinesterase inhibitory properties
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Novel arylpiperazine derivatives bearing lipophilic probes were designed, synthesized, and evaluated for their potential ability to interact with the 5-hydroxytryptamine3 (5-HT3) receptor. Most of the new compounds show subnanomolar 5-HT3 receptor affinity. Ester 6bc showing a picomolar Ki value is one of the most potent 5-HT 3 receptor ligands so far synthesized. The structure-affinity relationship study suggests the existence of a certain degree of conformational freedom of the amino acid residues interacting with the substituents in positions 3 and 4 of the quipazine quinoline nucleus. Thus, the tacrine-related heterobivalent ligand 60 was designed in an attempt to capitalize on the evidence of such a steric tolerance. Compound 6o shows a nanomolar potency for both the 5-HT3 receptor and the human AChE and represents the first example of a rationally designed high-affinity 5-HT3 receptor ligand showing nanomolar AChE inhibitory activity. Finally, the computational analysis performed on compound 6o allowed the rationalization of the structure-energy determinants for AChE versus BuChE selectivity and revealed the existence of a subsite at the boundary of the 5-HT3 receptor extracellular domain, which could represent a "peripheral" site similar to that evidenced in the AChE gorge.
- Cappelli, Andrea,Gallelli, Andrea,Manini, Monica,Anzini, Maurizio,Mennuni, Laura,Makovec, Francesco,Menziani, M. Cristina,Alcaro, Stefano,Ortuso, Francesco,Vomero, Salvatore
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p. 3564 - 3575
(2007/10/03)
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- Microwave-assisted synthesis of quinoline derivatives from isatin
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Microwave irradiation has been used for a rapid and efficient synthesis of quinoline-4-carboxylic acids 5a-g and 1,2,3,4-tetrahydroacridine-9-carboxylic acid (6) from the reaction of isatins 1-3 with acyclic and cyclic ketones in basic medium. 2-Hydroxyquinoline-4-carboxylic acid (11) was also obtained by irradiating a mixture of isatin 1 and malonic acid in AcOH. The esters of 5f and 11 and their respective hydrazides 8 and 13 were also prepared under MWI. Copyright Taylor & Francis, Inc.
- El Ashry, El Sayed H.,Ramadan, El Sayed,Hamid, Hamida Abdel,Hagar, Mohamed
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p. 2243 - 2250
(2007/10/03)
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- Some Derivatives of Benzazepine. Part III
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We report the synthesis by two routes, of hitherto unknown 3,4-epoxy-2,3,4,5-tetrahydrobenzazepine-2,5-dione and hence a new route to 2,3,4,5-tetrahydrobenzazepine-2,4,5-triones which are precursors of 2-quinolonecarboxylic acids.
- James, Robert A.,Kohn, Charlotte A.,Rees, Alun H.,Verschuren, Rex E.
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p. 793 - 795
(2007/10/02)
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- Carbostyril derivatives
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Disclosed are carbostyril derivatives and their salts of the formulas STR1 The compounds have anti-peptic ulcer effects, and are useful as a treating agent for curing peptic ulcers in the digestive system, such as ulcers in the stomach and in the duodenum. The compounds particularly have prophylaxis and curing effects for treating chronic ulcers, for example experimental acetic acid-induced ulcers and cautery ulcers, with both low toxicity and few side-effects. Also disclosed are processes for preparing the compounds and for preparing pharmaceutical compositions containing them.
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