- Identification and molecular modeling of new quinolin-2-one thiosemicarbazide scaffold with antimicrobial urease inhibitory activity
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Abstract: A new series of 6-substituted quinolin-2-one thiosemicarbazides 6a–j has been synthesized. The structure of the target compounds was proved by different spectroscopic and elemental analyses. All the designed final compounds were evaluated for their in vitro activity against the urease-producing R. mucilaginosa and Proteus mirabilis bacteria as fungal and bacterial pathogens, respectively. Moreover, all compounds were in vitro tested as potential urease inhibitors using the cup-plate diffusion method. Compounds 6a and 6b were the most active with (IC50 = 0.58 ± 0.15 and 0.43 ± 0.09?μM), respectively, in comparison with lead compound I (IC50 = 1.13 ± 0.00?μM). Also, the designed compounds were docked into urease proteins (ID: 3LA4 and ID: 4UBP) using Open Eye software to understand correctly about ligand–receptor interactions. The docking results revealed that the designed compounds can interact with the active site of the enzyme through multiple strong hydrogen bonds. Moreover, rapid overlay of chemical structures’ analysis was described to understand the 3D QSAR of synthesized compounds as urease inhibitors. The results emphasize the importance of polar thiosemicarbazide directly linked to 6-substituted quinolone moieties as promising antimicrobial urease inhibitors. Graphic abstract: [Figure not available: see fulltext.]
- Elbastawesy, Mohammed A. I.,El-Shaier, Yaseen A. M. M.,Ramadan, Mohamed,Brown, Alan B.,Aly, Ashraf A.,Abuo-Rahma, Gamal El-Din A.
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- New Quinoline-2-one/thiazolium bromide Derivatives; Synthesis, Characterization and Mechanism of Formation
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We report on the formation of new quinoline-2-one derived by thiazolium bromides from the reaction of 3-thiosemicarbazides derived by 2-quinolones with 2-bromoacetophenones. The structure of products was elucidated by mass, IR and NMR spectra together with elemental analysis. The mechanism of products formation was discussed.
- Mostafa, Sara M.,Aly, Ashraf A.,Sayed, Samia M.,Raslan, Mohamed A.,Ahmed, Amira E.,Nafady, Ayman,Ishak, Esam A.,Shawky, Ahmed M.,Abdelhafez, El-Shimaa M.N.
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- An efficient click synthesis of chalcones derivatized with two 1-(2-quinolon-4-yl)-1,2,3-triazoles
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Chalcones derivatized with 1-(2-quinolonyl)-1,2,3-triazoles were synthesized by reaction of 4-azido-2-quinolones with 1-phenyl-3-(4-propargyloxyphenyl)prop-2-en-1-one, or by aldol reaction of 4-{[1-(2-oxo-1,2-dihydroquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methoxy}benzaldehydes with acetophenone. Whereas, chalcones bearing two 1-(2-quinolonyl)-1,2,3-triazoles were synthesized by reaction of 1,3-bis(4-propargyloxyphenyl)prop-2-en-1-one with 4-azido-2-quinolones, or by aldol condensation between 4-{4-[(4-acetylphenoxy)methyl]-1H-1,2,3-triazol-1-yl}quinolin-2(1H)-ones and 4-{[1-(2-oxo-1,2-dihydroquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methoxy}benzaldehydes.
- Abdelhakem, Adel M.,Alshammari, Mohammed B.,Aly, Ashraf A.,Bakht, Md Afroz,Brown, Alan B.,El-Sheref, Essmat M.,Shawky, Ahmed M.
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p. 395 - 403
(2021/07/07)
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- Design and tests of prospective property predictions for novel antimalarial 2-aminopropylaminoquinolones
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There is a pressing need to improve the efficiency of drug development, and nowhere is that need more clear than in the case of neglected diseases like malaria. The peculiarities of pyrimidine metabolism in Plasmodium species make inhibition of dihydroorotate dehydrogenase (DHODH) an attractive target for antimalarial drug design. By applying a pair of complementary quantitative structure–activity relationships derived for inhibition of a truncated, soluble form of the enzyme from Plasmodium falciparum (s-PfDHODH) to data from a large-scale phenotypic screen against cultured parasites, we were able to identify a class of antimalarial leads that inhibit the enzyme and abolish parasite growth in blood culture. Novel analogs extending that class were designed and synthesized with a goal of improving potency as well as the general pharmacokinetic and toxicological profiles. Their synthesis also represented an opportunity to prospectively validate our in silico property predictions. The seven analogs synthesized exhibited physicochemical properties in good agreement with prediction, and five of them were more active against P. falciparum growing in blood culture than any of the compounds in the published lead series. The particular analogs prepared did not inhibit s-PfDHODH in vitro, but advanced biological assays indicated that other examples from the class did inhibit intact PfDHODH bound to the mitochondrial membrane. The new analogs, however, killed the parasites by acting through some other, unidentified mechanism 24–48?h before PfDHODH inhibition would be expected to do so.
- Clark, Robert D.,Morris, Denise N.,Chinigo, Gary,Lawless, Michael S.,Prudhomme, Jacques,Le Roch, Karine G.,Lafuente, Maria José,Ferrer, Santiago,Gamo, Francisco Javier,Gadwood, Robert,Woltosz, Walter S.
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p. 1117 - 1132
(2020/08/26)
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- Novel Pyrazoloquinolin-2-ones: Design, synthesis, docking studies, and biological evaluation as antiproliferative EGFR-TK inhibitors
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Two new series of diethyl 2-[2-(substituted-2-oxo-1,2-dihydroquinolin-4-yl)hydrazono]-succinates 6a-g and 1-(2-oxo-1,2-dihydroquinolin-4-yl)-1H-pyrazoles 7a-f have been designed and synthesized. The structures of the synthesized compounds were proved by IR, mass, NMR (2D) spectra and elemental analyses. The target compounds were evaluated for their in vitro cytotoxic activity against 60 cancer cell lines according to NCI protocol. Consequently, seven compounds were further examined against the most sensitive cell lines, leukemia CCRF-CEM, and MOLT-4. 5-Amino-1-(6-bromo-2-oxo-1,2-dihydroquinolin-4-yl)-1H-pyrazole-3,4-dicarbonitrile (7f) was the most active product, with IC50 = 1.35 uM and 2.42 uM against MOLT-4 and CCRF-CEM, respectively. Also, it showed a remarkable inhibitory activity compared to erlotinib on the EGFR TK with IC50 = 247.14 nM and 208.42 nM, respectively. Cell cycle analysis of MOLT-4 cells treated with 7f showed cell cycle arrest at G2/M phase (supported by Caspases, BAX and Bcl-2 studies) with a significant pro-apoptotic activity as indicated by annexin V-FITC staining. Moreover, the docking study indicated that both the pyrazole moiety and the quinolin-2-one ring showed good fitting into EGFR (PDB code: 1M17). In order to interpret SAR of the designed compounds, and provide a basis for further optimization, molecular docking of the synthesized compounds to known EGFR inhibitors was performed. The study illustrated the effect of several factors on the compounds’ activity.
- Elbastawesy, Mohammed A.I.,Aly, Ashraf A.,Ramadan, Mohamed,Elshaier, Yaseen A.M.M.,Youssif, Bahaa G.M.,Brown, Alan B.,El-Din A Abuo-Rahma, Gamal
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- BICYCLIC ARYL MONOBACTAM COMPOUNDS AND METHODS OF USE THEREOF FOR THE TREATMENT OF BACTERIAL INFECTIONS
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The present invention relates to bicyclic aryl monobactam compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein A1, L, M, W, X, Y, Z, RX and Rz are as defined herein. The present invention also relates to compositions which comprise a bicyclic aryl monobactam compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The invention further relates to methods for treating a bacterial infection comprising administering to the patient a therapeutically effective amount of a compound of the invention, either alone or in combination with a therapeutically effective amount of one or more beta-lactamase inhibitor compounds.
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Page/Page column 68
(2017/09/27)
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- Regioselective synthesis of 2-chloroquinoline based ethyl 4-(3-hydroxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylates and their In-Silico evaluation against P. Falciparum lactate dehydrogenase
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The reaction of various substituted 2, 4-dichloroquinolines with ethyl 4-(3-hydroxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate was carried out in the presence of K2CO3 as a mild and efficient base at controlled temperature leading to novel 2-chloroquinoline based polyhydroquinoline with high regioselectivity. All the synthesized compounds were characterized using IR, NMR, Mass spectral data and then subjected to an in-silico analysis against P. falciparum lactate dehydrogenase.
- Rajesh, Kancherla,Lavanya, Pandian,Iniyavan, Pethaperumal,Sarveswari, Sundaramoorthy,Ramaiah, Sudha,Anbarasu, Anand,Vijayakumar, Vijayaparthasarathi
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p. 789 - 797
(2015/12/01)
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- Synthesis of 6-methoxy-N 2,N 2,N 4,N 4,N 5,N 5-hexamethylquinoline-2,4,5-triamine - A new representative of quinoline proton sponges
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[Figure not available: see fulltext.] We report the synthesis of 4-chloro-2-methyl-5-nitro- and 2,4-dichloro-5-nitroquinolines, containing methoxy groups at positions 6 and 8. The reaction of these compounds with dimethylamine solution in alcohol was shown to produce not only aminodehalogenation products, but also resulted in nucleophilic substitution of the methoxy groups. The reduction of 6-methoxy-N 2,N 2,N 4,N 4-tetramethyl-5-nitroquinoline-2,4-diamine with subsequent methylation gave 6-methoxy-N 2,N 2,N 4,N 4,N 5,N 5-hexamethylquinoline-2,4,5-triamine, a new representative of quinoline proton sponges.
- Dyablo, Olga V.,Pozharskii, Alexander F.,Shmoilova, Elena A.,Savchenko, Aleksey O.
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p. 250 - 258
(2016/01/12)
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- 5-Methoxyquinoline derivatives as a new class of EZH2 inhibitors
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A series of quinoline derivatives was synthesized and biologically evaluated as Enhancer of Zeste Homologue 2 (EZH2) inhibitors. Structure-activity relationship (SAR) studies led to the discovery of 5-methoxy-2-(4-methyl-1,4-diazepan-1-yl)-N-(1-methylpiperidin-4-yl)quinolin-4-amine (5k), which displayed an IC50 value of 1.2 μM against EZH2, decreased global H3K27me3 level in cells and also showed good anti-viability activities against two tumor cell lines. Due to the low molecular weight and the fact that no quinoline derivative has been reported as an EZH2 inhibitor, this compound could serve as a lead compound for further optimization.
- Xiang, Pu,Jie, Hui,Zhou, Yang,Yang, Bo,Wang, Hui-Juan,Hu, Jing,Hu, Jian,Yang, Sheng-Yong,Zhao, Ying-Lan
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p. 7620 - 7636
(2015/05/20)
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- Syntheses and fluorescent properties of 6-methoxy-2-oxoquinoline-3,4- dicarbonitriles and 6,7-dimethoxy-2-oxoquinoline-3,4-dicarbonitriles
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4-Chlorocarbostyrils 3, 12, 17, 24, 26 with methoxy substituents in 6, 7, or 6,7-position react with potassium cyanide in a p-toluenesulfinate mediated reaction either to the highly fluorescent and stable 2-oxoquinoline-3,4- dicarbonitriles 6, 27, 29, 30 or at slightly lower temperatures to 4-monocarbonitriles 5, 13, 18. 4-Chlorocarbostyril 3 and lithium p-toluenesulfinate gave pure 4-toluenesulfonylquinolone 4, which reacted with potassium cyanide either to monocarbonitrile 5 or dicarbonitrile 6, depending on the reaction conditions. 4-Trifluoromethylquinolones 9 and 19 were prepared for fluorescence comparison from the appropriate methoxyaniline and 4,4,4-trifluoroacetoacetate. The fluorescence properties such as emission wavelengths and quantum yields of 6-methoxyderivatives 4, 5, 6, 9, 13 were studied and compared with those of 7-methoxy derivatives 18, 19 and 6,7-dimethoxyderivatives 27, 28, 29, 30. 6,7-Dimethoxy derivatives show best results, showing long-waved fluorescence spectra up to 520 nm and acceptable quantum yields up to 0.46 for 3,4-dicyano derivative 27 excited at 440 nm in acetonitrile.
- Enoua, Guy Crépin,Lahm, Günther,Uray, Georg,Stadlbauer, Wolfgang
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p. E263-E275
(2014/11/07)
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- Regioselective synthesis of novel 2-chloroquinoline derivatives of 1,4-dihydropyridines
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Highly regioselective reaction of some substituted 2,4-dichloroquinolines with symmetrical 1,4-dihydropyridines, leading to novel quinoline derivatives of DHPs, has been achieved in the presence of powdered K2CO 3, as a mild and efficient base, at moderate temperature. All the synthesized compounds were characterized by use of IR, NMR, and mass spectral data.
- Rajesh,Iniyavan,Sarveswari,Vijayakumar
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p. 1851 - 1866
(2014/05/06)
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- Ultrasound-promoted synthesis of novel 2-chloroquinolin-4-pyrimidine carboxylate derivatives as potential antibacterial agents
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Ultrasound-promoted reaction of substituted 2,4-dichloroquinolines (1) with ethyl 4-(3-hydroxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5- carboxylate (2) in the presence of K2CO3 as mild base at moderate temperatures leads
- Balaji,Rajesh,Kouser Ali, Shabana,Vijayakumar
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p. 1807 - 1815
(2013/06/05)
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- NOVEL SUBSTITUTED QUINOLINE COMPOUNDS AS S-NITROSOGLUTATHIONE REDUCTASE INHIBITORS
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The present invention is directed to novel quinoline compounds useful as S-nitrosoglutathione reductase (GSNOR) inhibitors, pharmaceutical compositions comprising such compounds, and methods of making and using the same.
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Page/Page column 78
(2012/04/23)
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- STEREOSELECTIVE METHODS, CATALYSTS AND INTERMEDIATES FOR THE SYNTHESIS OF (-)-NUTLIN-3 AND RELATED COMPOUNDS
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The present invention provides methods and intermediates are provided for the preparation of (?)-Nutlin-3. Methods and intermediates are also provided for the enantioselective addition of aryl nitromethanes to aldimines. Bis(amidine) catalysts for the use
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Page/Page column 14
(2012/04/18)
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- NOVEL SUBSTITUTED BICYCLIC AROMATIC COMPOUNDS AS S-NITROSOGLUTATHIONE REDUCTASE INHIBITORS
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The present invention is directed to novel substituted bicyclic aromatic compounds useful as S-nitrosoglutathione reductase (GSNOR) inhibitors, pharmaceutical compositions comprising such compounds, and methods of making and using the same.
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Page/Page column 95
(2012/06/30)
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- 4-thio substituted quinoline and naphthyridine compounds
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The present invention relates to 4-thio substituted quinoline and naphthyridine derivatives and processes for their preparation. The invention also related to methods for treating infection of Hepatitis C virus by administering a 4-thio substituted quinoline or naphthyridine derivative.
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Page/Page column 14
(2009/04/24)
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- 4-THIO SUBSTITUTED QUINOLINE AND NAPHTHYRIDINE COMPOUNDS
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The present invention relates to 4-thio substituted quinoline and naphthyridine derivatives and processes for their preparation. The invention also related to methods for treating infection of Hepatitis C virus by administering a 4-thio substituted quinoline or naphthyridine derivative.
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Page/Page column 35-36
(2008/06/13)
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- A convenient synthesis of 8,9,10,11-tetrahydrodibenzo[b,h] [1,6]naphthyridin-6(5H)ones
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Substituted 8,9,10,11-tetrahydrodibenzo[b,h][1,6]naphthyridin-6(5H)ones (5) have been synthesized by the condensation of 4-amino-3-formylquinolin-2(1H)ones (4) with cyclohexanone in presence of acetic acid and sulphuric acid. The precusors have been obtained by the animation of 4-chloro-3-formylquinolin-2(1H)ones (3).
- Arul Prakash,Rajendran
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p. 353 - 358
(2007/10/03)
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- A novel rearrangement of 3-arylisoxazol-5(4H)-ones: One-pot synthesis of new 2,4-dichloroquinoline-3-carbaldehydes
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Vilsmeier-Haack reaction, using a specific combination of phosphorus oxychloride and dimethylformamide, on 3-arylisoxazol-5(4H)ones 1 resulted in 2,4-dichloroquinoline-3-carbaldehydes 6 as the major products along with other minor products, through a novel rearrangement. Oxidation of 6 with alkaline potassium permanganate gave 2,4-dichloroquinoline-3-carboxylic acids 7. Decarboxylation of 6 and decarboxylation of 7 using aqueous sodium hydroxide yielded 2,4-dichloroquinolines 8. All the compounds were characterised by elemental and spectral analysis.
- Ashok,Sridevi,Umadevi
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p. 623 - 626
(2007/10/02)
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