- Discovery, synthesis and biological characterization of a series of: N -(1-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-1 H -pyrazol-5-yl)acetamide ethers as novel GIRK1/2 potassium channel activators
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The present study describes the discovery and characterization of a series of N-(1-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-1H-pyrazol-5-yl)acetamide ethers as G protein-gated inwardly-rectifying potassium (GIRK) channel activators. From our previous lead optimization efforts, we have identified a new ether-based scaffold and paired this with a novel sulfone-based head group to identify a potent and selective GIRK1/2 activator. In addition, we evaluated the compounds in tier 1 DMPK assays and have identified compounds that display nanomolar potency as GIRK1/2 activators with improved metabolic stability over the prototypical urea-based compounds. This journal is
- Alnouti, Yazen,Aretz, Christopher D.,Chhonker, Yashpal S.,Dhuria, Nikilesh V.,Du, Yu,Gautam, Nagsen,Hopkins, Corey R.,Kumar, Sushil,Lesiak, Lauren,Sharma, Swagat,Weaver, C. David
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p. 1366 - 1373
(2021/09/28)
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- Design and synthesis of α-phenoxy-N-sulfonylphenyl acetamides as Trypanosoma brucei Leucyl-tRNA synthetase inhibitors
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Human African trypanosomiasis (HAT), caused by the parasitic protozoa Trypanosoma brucei, is one of the fatal diseases in tropical areas and current medicines are insufficient. Thus, development of new drugs for HAT is urgently needed. Leucyl-tRNA synthetase (LeuRS), a recently clinically validated antimicrobial target, is an attractive target for development of antitrypanosomal drugs. In this work, we report a series of α-phenoxy-N-sulfonylphenyl acetamides as T. brucei LeuRS inhibitors. The most potent compound 28g showed an IC50 of 0.70 μM which was 250-fold more potent than the starting hit compound 1. The structure-activity relationship was also discussed. These acetamides provided a new scaffold and lead compounds for the further development of clinically useful antitrypanosomal agents.
- Xin, Weixiang,Li, Zezhong,Wang, Qing,Du, Jin,Zhu, Mingyan,Zhou, Huchen
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- Design and Synthesis of Novel 4-Hydroxyl-3-(2-phenoxyacetyl)-pyran-2-one Derivatives for Use as Herbicides and Evaluation of Their Mode of Action
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In order to develop a novel herbicide containing the β-triketone motif, a series of 4-hydroxyl-3-(2-phenoxyacetyl)-pyran-2-one derivatives were designed and synthesized. The bioassay results showed that compound II15 had good pre-emergent herbicidal activity even at a dosage of 187.5 g ha-1. Moreover, compound II15 showed a broader spectrum of weed control when compared with a commercial herbicide 2,4-dichlorophenoxyacetic acid (2,4-D), and displayed good crop safety to Triticum aestivum L. and Zea mays Linn. when applied at 375 g ha-1 under pre-emergence conditions, which indicated its great potential as a herbicide. More importantly, studying the molecular mode of action of compound II15 revealed that the novel triketone structure is a proherbicide of its corresponding phenoxyacetic acid auxin herbicide, which has a herbicidal mechanism similar to that of 2,4-D. The present work indicates that the 4-hydroxyl-3-(2-phenoxyacetyl)-pyran-2-one motif may be a potential lead structure for further development of novel auxin-type herbicides.
- Lei, Kang,Li, Pan,Yang, Xue-Fang,Wang, Shi-Ben,Wang, Xue-Kun,Hua, Xue-Wen,Sun, Bin,Ji, Lu-Sha,Xu, Xiao-Hua
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p. 10489 - 10497
(2019/10/02)
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- THERAPEUTIC COMPOUNDS AND METHODS OF USE THEREOF
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The invention provides a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein the variables X, Y1-Y5, R1, R2, R3, R4, and Het have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.
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Paragraph 0512; 0515; 0516
(2018/04/26)
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- CDC42 INHIBITOR AND USES THEREOF
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A compound having the structure of formula I and its use as a Cdc42 inhibitor. Morphological analyses of filopodia, western blots of Ccd42 phosphorylation, and the experiments on cellular wound healing and on growth cone formation all demonstrate that the compound provided in the present invention is able to inhibit all tested Cdc42-mediated processes. The compounds effectively inhibited the effects of Cdc42 and effectively inhibit Cdc42-related cellular functions involving actin, such as Golgi organization and cell movement.
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Page/Page column
(2014/05/06)
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- Cdc42 Inhibitor and Uses Thereof
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Compounds which inhibit the small G protein Rho GTPase cell division cycle protein Cdc42 are provided. Morphological analyses of filopodia, western blots of Ccd42 phosphorylation, and effects on cellular wound healing and on growth cone formation all demo
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- Discovery of N-(4-sulfamoylphenyl)thioureas as Trypanosoma brucei leucyl-tRNA synthetase inhibitors
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Human African trypanosomiasis (HAT) is one of the most neglected diseases in the tropic regions, which is fatal if not treated in time. There is an urgent need for new therapeutics, especially those in new chemical classes. Leucyl-tRNA synthetase (LeuRS) has been paid much attention as a recently clinically validated antimicrobial target. Our group has previously reported T. brucei LeuRS (TbLeuRS) inhibitors, including benzoxaboroles targeting the editing site and pyrrolinones targeting the synthetic site. Here we report the discovery of N-(4-sulfamoylphenyl)thioureas as a new class of TbLeuRS inhibitors. The R1 and R2 groups, reminiscent of the leucyl and adenyl regions of aa-AMP and aa-AMS, were optimized to result in a significant 13-fold increase of inhibitory activity (compound 19, IC 50 = 13.7 μM). Aided by ligand-protein docking, the 1,3-substitution at the central phenyl ring was predicted and proved to give significantly improved activity (59, IC50 = 1.1 μM). This work provided a new scaffold for the exploration of novel inhibitors against TbLeuRS, which may become potential therapeutics for the treatment of HAT.
- Zhang, Fenglong,Du, Jin,Wang, Qing,Hu, Qinghua,Zhang, Jiong,Ding, Dazhong,Zhao, Yaxue,Yang, Fei,Wang, Enduo,Zhou, Huchen
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p. 5310 - 5324
(2013/08/23)
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- Herbicidal aryloxyacetic acid derivatives
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Aryloxyacetic acid derivatives of the formula STR1 where R1 is H, CH3, Cl, Br, F, or NO2 ; R2 is H or Cl; R3 is H, CH3 C(CH3)3, Cl, Br or NO2 ; R4/sub
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