- Lead Optimization of Influenza Virus RNA Polymerase Inhibitors Targeting PA-PB1 Interaction
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Influenza viruses are responsible for contagious respiratory illnesses in humans and cause seasonal epidemics and occasional pandemics worldwide. Previously, we identified a quinolinone derivative PA-49, which inhibited the influenza virus RNA-dependent RNA polymerase (RdRp) by targeting PA-PB1 interaction. This paper reports the structure optimization of PA-49, which resulted in the identification of 3-((dibenzylamino)methyl)quinolinone derivatives with more potent anti-influenza virus activity. During the optimization, the hit compound 89, which was more active than PA-49, was identified. Further optimization and scaffold hopping of 89 led to the most potent compounds 100 and a 1,8-naphthyridinone derivative 118, respectively. We conclusively determined that compounds 100 and 118 suppressed the replication of influenza virus and exhibited anti-influenza virus activity against both influenza virus types A and B in the range of 50% effective concentration (EC50) = 0.061-0.226 μM with low toxicity (50% cytotoxic concentration (CC50) >10 μM).
- Mizuta, Satoshi,Otaki, Hiroki,Ishikawa, Takeshi,Makau, Juliann Nzembi,Yamaguchi, Tomoko,Fujimoto, Takuya,Takakura, Nobuyuki,Sakauchi, Nobuki,Kitamura, Shuji,Nono, Hikaru,Nishi, Ryota,Tanaka, Yoshimasa,Takeda, Kohsuke,Nishida, Noriyuki,Watanabe, Ken
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p. 369 - 385
(2021/12/27)
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- Synthesis and evaluation of Zn(II) dithiocarbamate complexes as potential antibacterial, antibiofilm, and antitumor agents
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Four complexes having the formula [Zn(L)2] [L1 = (C18H20NS2 –), N-(4-isopropyl-benzyl)-(benzyl)-dithiocarbamate], [L2 = (C10H12NS2 –), N-(benzyl)-(ethyl)-dithiocarbamate], [L3 = (C19H22ONS2 –), N-(4-isopropyl-benzyl)-(4-methoxy-benzyl)-dithiocarbamate], and [L4 = (C16H16NS2 –), N-(benzyl)-(4-methyl-benzyl)-dithiocarbamate] have been contemplated, synthesized, and characterized by elemental analysis and IR, 1H, 13C NMR and UV–visible absorption spectra. All Zn(II) complexes have similar geometry and coordination number. Complex A2 (with ligand L2) crystallizes in triclinic system with space group P-1 having distorted square pyramidal geometry which was stabilized by weak C–H···π and C–H···S intramolecular interactions. The antibacterial, antibiofilm, and antitumor activities of the complexes have been screened and A2 and A3 showed their prominence. Interestingly, both A2 and A3 showed more killing potential against multi-drug resistant gram-positive isolates with MIC indices of 16 μg mL?1 and 16 μg mL?1, respectively, against both MRSA and MSSA, while the antitumor agent A3 showed its prominence with GI50 and LC50 41.15 and 133.73 μg mL?1, respectively.
- Maurya, Vinay Kumar,Singh, Ashish Kumar,Singh, Ravi Pratap,Yadav, Shivangi,Kumar, Krishna,Prakash, Pradyot,Prasad, Lal Bahadur
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p. 3338 - 3358
(2019/11/26)
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- Trisubstituted sulfonamides: A new chemotype for development of potent and selective CB2 receptor inverse agonists
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An extensive exploration of the structure-activity relationship of a trisubstituted sulfonamide series led to the identification of 39, which is a potent and selective CB2 receptor inverse agonist [K i(CB2) = 5.4 nM, and Ki(CB1) = 500 nM]. The functional properties measured by cAMP assays indicated that the selected compounds were CB2 inverse agonists with high potency values (for 34, EC50 = 8.2 nM, and for 39, EC50 = 2.5 nM). Furthermore, an osteoclastogenesis bioassay indicated that trisubstituted sulfonamide compounds showed great inhibition of osteoclast formation.
- Ouyang, Qin,Tong, Qin,Feng, Rentian,Myint, Kyaw-Zeyar,Yang, Peng,Xie, Xiang-Qun
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p. 387 - 392
(2013/06/26)
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- Synthesis of α-amino acids through samarium(II) iodide promoted reductive coupling of nitrones with CO2
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Several N-benzylnitrones reacted with carbon dioxide in the presence of samarium(II) iodide leading to α-amino acids as the products of reductive C-C coupling. The best selectivities were observed at a carbon dioxide pressure of 50 bar at ambient temperature. The influences of different functional groups in the nitrone backbone and of the coordinating additives to samarium(II) iodide on the product distribution were investigated. The racemic α-amino acids were obtained in up to 70% yield based on HPLC data. A novel approach to the synthesis ofα-amino acids is disclosed, involvingC-carboxylation of nitrones by gaseous CO2 under reductive coupling reaction conditions (SmI2, 0.1 M in THF) at ambient temperature and 50 bar of CO 2 pressure. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
- Prikhod'Ko, Alexander,Walter, Olaf,Zevaco, Thomas A.,Garcia-Rodriguez, Jaime,Mouhtady, Omar,Py, Sandrine
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supporting information; experimental part
p. 3742 - 3746
(2012/09/25)
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