- SUBSTITUTED QUINOLINONYL PIPERAZINE COMPOUNDS USEFUL AS T CELL ACTIVATORS
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Disclosed are compounds of Formula (I) or a salt thereof, wherein: R1, R2, R3, R4, R5, R6, and m are defined herein. Also disclosed are methods of using such compounds to inhibit the activi
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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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- Discovery of 4-hydroxy-2-oxo-1,2-dihydroquinolines as potential inhibitors of Streptococcus pneumoniae, including drug-resistant strains
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New therapies for treating drug-resistant pneumococcal infections are urgently needed. The novel scaffold 6-hydroxy-4-oxo-1,2-dihydro-4H-quinoline was shown to have similar efficacies against all three different serotypes of S. pneumoniae, ATCC 49617 (19F), ATCC BAA-1663 (15B), and ATCC 700904 (19A), in a resazurin-based high-throughput screen using the Korea Chemical Bank library. Further studies to identify a new lead with this scaffold, including tricyclic pyrrolo[3,2,1-ij]quinolone and pyrido[3,2,1-ij]quinolone derivatives, led to the identification of 6d, 7d and 12a. Compound 6d (IC50 = 0.92, 0.75, and 0.77 μM), 7d (IC50 = 0.57, 0.66, and 0.38 μM) and 12a (IC50 = 0.27, 1.03, and 0.62 μM) showed submicromolar IC50 values against 19F, 15B, and 19A, respectively, and thus serve as a starting point for further optimization. While some of compounds in this series exhibited acceptable pharmacokinetic profiles in preliminary in vivo rat experiments, the most active compound 12a showed poor solubility and high plasma protein binding. Our current research efforts are focused on optimizing compounds to improve physicochemical properties as well as potency.
- Huddar, Srigouri,Jang, Soojin,Kim, Hyung Jun,Lee, Sunkyung,Park, Chul Min
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supporting information
(2020/03/10)
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- Pharmaceutical composition for prevention or treatment of pneumonia comprising dihydroquinoline carboxamide derivative or pharmacurically acceptable salt thereof as an active ingredient
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Disclosed is a pharmaceutical composition for preventing or treating pneumonia comprising a dihydroquinoline carboxamide derivative or a pharmaceutically acceptable salt thereof as an active component. The pharmaceutical composition has excellent antimicr
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Paragraph 0363; 0364-0366
(2019/08/28)
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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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supporting information
p. 1166 - 1170
(2018/03/21)
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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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p. 1315 - 1323
(2018/06/29)
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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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p. 400 - 410
(2016/10/03)
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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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p. 1069 - 1079
(2017/01/11)
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- Design, synthesis and biological characterization of a new class of osteogenic (1H)-quinolone derivatives
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Smoothened (Smo) is the signal transducer of the Hedgehog (Hh) pathway and its stimulation is considered a potential powerful tool in regenerative medicine to treat severe tissue injuries. Starting from GSA-10, a recently reported Hh activator acting on Smo, we have designed and synthesized a new class of quinolone-based compounds. Modification and decoration of three different portions of the original scaffold led to compounds able to induce differentiation of multipotent mesenchymal cells into osteoblasts. The submicromolar activity of several of these new quinolones (0.4–0.9?μM) is comparable to or better than that of SAG and purmorphamine, two reference Smo agonists. Structure-activity relationships allow identification of several molecular determinants important for the activity of these compounds.
- Manetti, Fabrizio,Petricci, Elena,Gabrielli, Annalisa,Mann, Andrè,Faure, Hélène,Gorojankina, Tatiana,Brasseur, Laurent,Hoch, Lucile,Ruat, Martial,Taddei, Maurizio
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p. 747 - 757
(2016/07/21)
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- Heterocyclic GSK-3 Allosteric Modulators
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The present invention relates to heterocyclic substituted quinoline derivatives as allosteric inhibitors of the glycogen synthase kinase-3 (GSK-3) enzyme. Therefore, these compounds are useful for the manufacturing of a medicament designed for the treatme
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Paragraph 0134; 0135; 0136
(2015/03/04)
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- Quinolone-benzylpiperidine derivatives as novel acetylcholinesterase inhibitor and antioxidant hybrids for Alzheimer Disease
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Design, synthesis and evaluation of new acetylcholinesterase inhibitors by combining quinolinecarboxamide to a benzylpiperidine moiety are described. Then, a series of hybrids have been developed by introducing radical scavengers. Molecular modeling was performed and structure activity relationships are discussed. Among the series, most potent compounds show effective AchE inhibitions, high selectivities over butyrylcholinesterase and high radical scavenging activities. On the basis of this work, the ability of quinolone derivatives to serve in the design of N-benzylpiperidine linked multipotent molecules for the treatment of Alzheimer Disease has been established.
- Pudlo, Marc,Luzet, Vincent,Ismaili, Lhassane,Tomassoli, Isabelle,Iutzeler, Anne,Refouvelet, Bernard
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p. 2496 - 2507
(2014/05/06)
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- HETEROCYCLIC GSK-3 ALLOSTERIC MODULATORS
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The invention relates to heterocyclic derivatives of substituted quinolines as allosteric inhibitors of the glycogen synthase kinase 3 (GSK-3) enzyme. Thus, said compounds can be used in the production of a drug for the treatment and/or prevention of diseases in which GSK-3 is involved, such as: neurodegenerative diseases, inflammatory diseases, cancer and diabetes, as well as to promote a plurality of regenerative processes..
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Paragraph 0049
(2014/09/03)
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- Synthesis of 3,4-disubstituted quinolin-2-(1H)-ones via palladium-catalyzed decarboxylative arylation reactions
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The Pd-catalyzed decarboxylative cross-coupling reaction of 4-substituted quinolin-2(1H)-one-3-carboxylic acids with (hetero)aryl halides is described. With palladium(II) bromide and triphenylarsine ligand as the catalyst system, a variety of 4-substituted 3-(hetero)aryl quinolin-2(1 H)-ones and related heterocycles, such as 4-substituted 3-arylcoumarins can be prepared in good to excellent yields. Copyright
- Carrer, Amandine,Brion, Jean-Daniel,Messaoudi, Samir,Alami, Mouad
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supporting information
p. 2044 - 2054
(2013/08/23)
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- 1,2-DIHYDRO-4-HYDROXY-2-OXO-QUINOLINE-3-CARBOXANILIDES AS AHR ACTIVATORS.
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The present invention relates to compounds which are 1, 2-dihydro-4- hydroxy-2-oxo-quinoline-3-carboxanilides, their thieno-pyridone analogs, and prodrugs thereof. This invention specifically relates to such derivatives containing an N-hydrogen in the carboxanilide moiety and which exhibit modulating activity towards the aromatic hydrocarbon receptor (AhR), and, specifically, also to prodrugs thereof. The present invention also relates to use of said compounds as a medicament, and for the treatment of cancer, autoimmune disorders and other disorders with an immunological component, and a pharmaceutical composition comprising one or more of said compounds and a method of treatment.
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Page/Page column 30
(2012/05/04)
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- 4-hydroxy-2-quinolones 199*. Use of N,N'-dicyclohexylcarbodiimide in the synthesis of ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates
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A novel method has been developed for the synthesis of 4-hydroxy-2-oxo-1,2- dihydroquinoline-3-carboxylic acids esters based on the use of monoethyl malonate as an acylating agent in the presence of N,N'-dicyclohexylcarbodiimide and characterized by high yields and purity for the final products. Practical recommendations are given for the removal of specific admixtures.
- Ukrainets,Golik,Bevz,Gorokhova
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p. 833 - 837
(2012/04/10)
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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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experimental part
p. 1 - 10
(2011/02/27)
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- Alkylidenephosphoranes in heterocyclic synthesis: Reactivity of benzoxazinones with resonance-stabilized phosphorus ylides
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2H-3,1-Benzoxazine-2,4(1H)-dione and its N-methyl analogue react with alkylidenephosphoranes to give substituted quinolines and benzazepines as well as indanone and furan derivatives. Reaction mechanisms to explain the formation of products obtained are outlined. Georg Thieme Verlag Stuttgart.
- Kamel, Azza A.,Abdou, Wafaa M.
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p. 1269 - 1273
(2007/12/27)
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- INHIBITORS OF MACROPHAGE MIGRATION INHIBITORY FACTOR AND METHODS FOR IDENTIFYING THE SAME
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Inhibitors of MIF are provided which have utility in the treatment of a variety of disorders, including the treatment of pathological conditions associated with MIF activity. The inhibitors of MIF have the following structures (Ia), (Ib) including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, wherein n, R1, R2, R3, R4, X, and Z are as defined herein. Compositions containing an inhibitor of MIF in combination with a pharmaceutically acceptable carrier are also provided, as well as methods for use of the same.
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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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- A novel short-step synthesis of functionalized 4-hydroxy-2-quinolones using a 1-hydroxybenzotriazole methodology
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A novel method for the synthesis of 3-substituted 4-hydroxy-1-methyl- and 1-phenyl-2-quinolones is presented. The compounds are produced in a one-step reaction in very good yields (51-76%). The major advantage of the methodology is the short time for the
- Zikou, Lamprini,Athanasellis, Giorgos,Detsi, Anastasia,Zografos, Alexandros,Mitsos, Christos,Igglessi-Markopoulou, Olga
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p. 1505 - 1508
(2007/10/03)
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- Structure-activity relationships studies of the anti-angiogenic activities of linomide
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The synthesis and anti-angiogenic activities of linomide and its analogues are reported. Three of the analogues are 3.3-69 times more potent than linomide at inhibiting blood vessel formation in the CAM angiogenesis assay. These compounds possessed consid
- Shi, Jiandong,Xiao, Zili,Ihnat, Michael A.,Kamat, Chandrashekhar,Pandit, Bulbul,Hu, Zhigen,Li, Pui-Kai
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p. 1187 - 1189
(2007/10/03)
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- Synthesis of N-Pyridinyl(methyl)-1,2-dihydro-4-hydroxy-2-oxoquinoline-3-carboxamides and analogues and their anti-inflammatory activity in mice and rats
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The topical anti-inflammatory activity of a series of N-pyridinyl(methyl)1,2-dihydro-4-hydroxy-2-oxoquinoline-3-carboxamides, analogues of roquinimex, has been evaluated by measuring their inhibitory effect in the phorbol myristate acetate (PMA)-induced m
- Collin,Robert,Duflos,Wielgosz,Le Baut,Robin-Dubigeon,Grimaud,Lang,Petit
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p. 417 - 423
(2007/10/03)
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- Synthesis of new pyrazolo[4,3-c]quinolin-3-one derivatives and some oxazolo[4,5-c]quinoline-2,4-diones
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The new pyrazolo[4,3-c]quinolin-3-one derivatives 3a-c and 6a-c were prepared by the following three steps: first the preparation of ethyl 4- hydroxyquinoline-3-carboxylate derivatives 1 and 4 by reaction of isatoic anhydrides and ethyl malonate and ethyl acetoacetate respectively, then chloration of 1 and 4 with phosphorus oxychloride to give 2 and 5 and finally the condensation of 2 and 5 with hydrazine and its derivatives. In addition, the successful synthesis of oxazolo[4,5-c]quinoline-2,4-diones 9a-f are reported.
- Ismaili, Lhassane,Refouvelet, Bernard,Robert, Jean Francois
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p. 719 - 722
(2007/10/03)
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- 4-HYDROXY-2-QUINOLONES. 22. SYNTHESIS AND BIOLOGICAL PROPERTIES OF 1-ALKYL(ARYL)-2-OXO-3-CERBETHOXY-4-HYDROXYQUINOLINES AND THEIR DERIVATIVES
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The presently known method for obtaining ethyl esters of 1-alkyl(or aryl)-2-oxo-4-hydroxyquinoline-3-carboxylic acids and their derivatives has been improved.Results are presented from an investigation of the anticoagulant, analgesic, and antiinflammatory activities of the synthesized compounds.
- Ukrainets, I.V.,Gorokhova, O.V.,Taran, S.G.,Bezuglyi, P.A.,Turov, A.V.,et al.
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p. 829 - 836
(2007/10/02)
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- 4-Hydroxy-2-quinolones. 3. Synthesis and Physicochemical Properties of 1-R-3-Carbethoxy-4-hydroxy-2-quinolones
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1-R-3-Carbethoxy-4-hydroxy-2-quinolones were synthesized by intramolecular cyclization of N-R-2-carbalkoxymalonanilic acids by the Dieckmann reaction.The possibility and advantages of conducting this reaction in aqueous medium were demonstrated.The mutual
- Ukrainets, I. V.,Bezuglyi, P. A.,Treskach, V. I.,Turov, A. V.,Slobodzyan, S. V.
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p. 534 - 538
(2007/10/02)
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- Pharmaceutical preparation and use of 4-hydroxy-2-quinolinone-3-carboxylic acid esters
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Disclosed are compounds which are 4-hydroxy-2-quinolinone-3-carboxylic acid esters, e.g., 1-methyl-4-hydroxy-2-quinolinone-3-carboxylic acid ethyl ester, useful as anti-allergic agents and intermediates for 1-alkyl-4-alkoxy-quinolin-2(1H)-ones, and prepared by reacting an isatoic anhydride with an alkali metal salt of a malonic ester.
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