614-61-9Relevant academic research and scientific papers
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
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
, p. 1366 - 1373 (2021/09/28)
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
Design and synthesis of α-phenoxy-N-sulfonylphenyl acetamides as Trypanosoma brucei Leucyl-tRNA synthetase inhibitors
Xin, Weixiang,Li, Zezhong,Wang, Qing,Du, Jin,Zhu, Mingyan,Zhou, Huchen
, (2019/11/26)
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.
Synthesis and herbicidal activities of aryloxyacetic acid derivatives as HPPD inhibitors
Huang, Hao,Liu, Jian-Min,Shu, Lei,Wang, Man-Man,Yan, Yi-Le,Zhang, Da-Yong,Zhang, Jian-Qiu
, p. 233 - 247 (2020/03/27)
A series of aryloxyacetic acid derivatives were designed and synthesized as 4-hydoxyphenylpyruvate dioxygenase (HPPD) inhibitors. Preliminary bioassay results reveal that these derivatives are promising Arabidopsis thaliana HPPD (AtHPPD) inhibitors, in particular compounds I12 (Ki = 0.011 μM) and I23 (Ki = 0.012 μM), which exhibit similar activities to that of mesotrione, a commercial HPPD herbicide (Ki = 0.013 μM). Furthermore, the newly synthesized compounds show significant greenhouse herbicidal activities against tested weeds at dosages of 150 g ai/ha. In particular, II4 exhibited high herbicidal activity for pre-emergence treatment that was slightly better than that of mesotrione. In addition, compound II4 was safe for weed control in maize fields at a rate of 150 g ai/ha, and was identified as the most potent candidate for a novel HPPD inhibitor herbicide. The compounds described herein may provide useful guidance for the design of new HPPD inhibiting herbicides and their modification.
Dechlorination of 2,4-dichlorophenoxyacetic acid using biochar-supported nano-palladium/iron: Preparation, characterization, and influencing factors
Zhou, Hongyi,Huang, Ning,Zhao, Yongkang,Baig, Shams Ali,Xiang, Junchao
, (2020/09/23)
In the present study, peanut shell, a green waste raw material, was used to prepare biochar (BC) and to obtain BC-supported nano-palladium/iron (BC-nPd/Fe) composites for removing 2,4-dichlorophenoxyacetic acid (2,4-D) from water. Characterization analysis demonstrated that nPd/Fe particles were well dispersed on the BC surface with weakened magnetic properties. The average particle diameter and specific surface area of nPd/Fe were 101.3 nm and 6.7 m2 g?1, whereas the corresponding values of the BC-nPd/Fe materials were 88.8 nm and 14.8 m2 g?1, respectively. Several factors were found to influence the dechlorination of 2,4-D, including the weight ratio of BC to Fe, Pd loading ratio, initial solution pH, 2,4-D concentration, and reaction temperature. Dechlorination results indicated that the 2,4-D removal and phenoxyacetic acid (PA) generation rates were 44.1% and 20.1%, respectively, in the nPd/Fe system, and 100.0% and 92.1%, respectively, in the BC-nPd/Fe system. The dechlorination of 2,4-D was well described by the pseudo-first-order kinetic model (R2 > 0.97), and the observed rate constants kobs were 0.0042 min (nPd/Fe) and 0.0578 min (BC-nPd/Fe), respectively. The reaction mechanism indicated that the dechlorination hydrogenation was the main process to remove 2,4-D from water in the BC-nPd/Fe system. In addition, BC inhibited the formation of a passivation layer on the particle surface during the reaction, thus maintaining the high reactivity of BC-nPd/Fe. The easy preparation technique, high 2,4-D dechlorination capacity, and mild reaction conditions suggest that BC-nPd/Fe may be a promising alternative composite to remove 2,4-D from water.
Optimizing TRPM4 inhibitors in the MHFP6 chemical space
Delalande, Clémence,Awale, Mahendra,Rubin, Matthias,Probst, Daniel,Ozhathil, Lijo C.,Gertsch, Jürg,Abriel, Hugues,Reymond, Jean-Louis
, p. 167 - 177 (2019/02/01)
We recently reported 4-chloro-2-(2-chlorophenoxy)acetamido)benzoic acid (CBA) as the first potent inhibitor of TRPM4, a cation channel implicated in cardiac diseases and prostate cancer. Herein we report a structure-activity relationship (SAR) study of CBA resulting in two new potent analogs. To design and interpret our SAR we used interactive color-coded 3D-maps representing similarities between compounds calculated with MHFP6 (MinHash fingerprint up to six bonds), a new molecular fingerprint outperforming other fingerprints in benchmarking virtual screening studies. We further illustrate the general applicability of our method by visualizing the structural diversity of active compounds from benchmarking sets in relation to decoy molecules and to drugs. MHFP6 chemical space 3D-maps might be generally helpful in designing, interpreting and communicating the results of SAR studies. The modified WebMolCS is accessible at http://gdb.unibe.ch and the code is available at https://github.com/reymond-group/webMolCS for off-line use.
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
Lei, Kang,Li, Pan,Yang, Xue-Fang,Wang, Shi-Ben,Wang, Xue-Kun,Hua, Xue-Wen,Sun, Bin,Ji, Lu-Sha,Xu, Xiao-Hua
, p. 10489 - 10497 (2019/10/02)
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.
Click Chemistry-Assisted Synthesis of a β- D -Galactose-Targeted SiO2@RC Shell-Core Structure as a Nanoplatform for Metal-Based Complex Delivery
Xu, Xiuling,Hu, Fan,Shuai, Qi
supporting information, p. 10694 - 10701 (2018/09/13)
A facile reversed-phase microemulsion method was used to synthesize shell-core nanospheres of SiO2@RCs (SiO2-encapsuled rare-earth metal complexes). β-d-Galactose was then grafted onto the surfaces of the nanospheres through the copper(I)-catalyzed azide-alkyne cycloaddition click reaction for targeted delivery. The chemical characteristics and surface profiles of the nanocarriers were investigated by Fourier transform infrared spectroscopy, dynamic light scattering, transmission electron microscopy, and scanning electron microscopy. A high-efficiency microwave synthesis method was applied to prepare five complex cores by the reaction of different rare-earth metal salts with two isomeric ligands, o-CPA (2-chlorophenoxyacetic acid) and m-CPA (3-chlorophenoxyacetic acid). The crystal structures of the five synthesized RC cores were confirmed through X-ray diffraction, which revealed the formulas of five RCs, [Dy(o-CPA)3(H2O)]·H2O RC1, [Ho(o-CPA)3(H2O)]·H2O RC2, 2[Er(m-CPA)3(H2O)]·3H2O RC3, 2[Gd(m-CPA)3(H2O)]·3H2O RC4, and [Ce2(m-CPA)6(H2O)3]·2H2O RC5. An in vitro cell study revealed that all RCs exhibited certain anticancer activities. RC2, in particular, showed the strongest cytotoxicity against HepG2 cells. The enhanced cell permeability and drug retention considerably improved the cytotoxicity of all SiO2@RC2-gal relative to that of RC2. The selective uptake of the β-d-galactose-conjugated nanospheres by HepG2 cells through mechanisms mediated by cell surface receptors resulted in fewer side effects on extrahepatic tissues. Our contribution provides a novel design concept of a target SiO2@RCs-gal nanocarrier for delivering affordable antitumor complexes in cancer therapy.
Facile microwave synthesis, structural diversity and herbicidal activity of six novel alkaline-earth metal complexes (AECs) based on skeletal isomerization chlorophenoxyacetic acids
Xu, Xiuling,Hu, Fan,Ma, Yuwei,Gao, Jinming,Shuai, Qi
, p. 4155 - 4166 (2018/03/21)
Six novel AECs of [Sr(o-CPA)2(H2O)4]·(o-CPA) 1, [Ba(o-CPA)2(H2O)]·H2O 2, [Sr(m-CPA)2(H2O)4]·(m-CPA) 3, [Ba(m-CPA)2(H2O)4]2·2(m-CPA)·H2O 4, [Sr(p-CPA)2(H2O)] 5 and [Ba(p-CPA)2(H2O)] 6 (o-CPA = 2-chlorophenoxyacetic acid, m-CPA = 3-chlorophenoxyacetic acid and p-CPA = 4-chlorophenoxyacetic acid) were synthesized by a facile microwave-assistant reaction. The solid-state structures were well established by X-ray crystallography and routine analyses of Fourier transform infrared, elemental analysis, field emission scanning electron microscope (FESEM) and thermogravimetric analysis. The structure data reveal that complexes of 1, 3 and 4 are one-dimensional chains with a zigzag arrangement, while 2, 5 and 6 are (4, 4) rhomboid two-dimensional grid structures. It is noticed that the carboxyl group in these complexes displays multiple coordination modes of μ2-η1:η1 (1, 2, 3, 4, 5 and 6), μ3-η1:η2 (1, 2, 3 and 4), μ2-η1:η2 (2), μ3-η2:η2 (5 and 6). Interestingly, the oxygen atoms of flexible -OCH2- in phenoxy groups take part in coordination behavior with metal centers through the rotation of the C-O and C-C bonds in complexes 2, 5 and 6, while only carboxyl group coordination can be found in complexes 1, 3 and 4. FESEM images indicate that the surface appearances of complexes are totally different from ligands after coordination. All ligands and complexes were evaluated for activity as plant-growth inhibitors against Amaranth (Amaranthus spp.) and barnyard grass. Compared with ligands, complexes 1, 3 and 4 exhibited better response index (RI) values of Shoot elongation against barnyard grass. Moreover, complexes 1, 3 and 4 demonstrated a higher inhibitory activity than 2, 5 and 6. It is significant to develop a new kind of environmentally-friendly herbicide based on these kinds of complexes for their low toxicity and high efficiency.
Identification of potent and selective small molecule inhibitors of the cation channel TRPM4
Ozhathil, Lijo Cherian,Delalande, Clémence,Bianchi, Beatrice,Nemeth, Gabor,Kappel, Sven,Thomet, Urs,Ross-Kaschitza, Daniela,Simonin, Céline,Rubin, Matthias,Gertsch, Jürg,Lochner, Martin,Peinelt, Christine,Reymond, Jean-Louis,Abriel, Hugues
, p. 2504 - 2519 (2018/05/03)
Background and Purpose: TRPM4 is a calcium-activated non-selective cation channel expressed in many tissues and implicated in several diseases, and has not yet been validated as a therapeutic target due to the lack of potent and selective inhibitors. We sought to discover a novel series of small-molecule inhibitors by combining in silico methods and cell-based screening assay, with sub-micromolar potency and improved selectivity from previously reported TRPM4 inhibitors. Experimental Approach: Here, we developed a high throughput screening compatible assay to record TRPM4-mediated Na+ influx in cells using a Na+-sensitive dye and used this assay to screen a small set of compounds selected by ligand-based virtual screening using previously known weakly active and non-selective TRPM4 inhibitors as seed molecules. Conventional electrophysiological methods were used to validate the potency and selectivity of the hit compounds in HEK293 cells overexpressing TRPM4 and in endogenously expressing prostate cancer cell line LNCaP. Chemical chaperone property of compound 5 was studied using Western blots and electrophysiology experiments. Key Results: A series of halogenated anthranilic amides were identified with TRPM4 inhibitory properties with sub-micromolar potency and adequate selectivity. We also showed for the first time that a naturally occurring variant of TRPM4, which displays loss-of-expression and function, is rescued by the most promising compound 5 identified in this study. Conclusions and Implications: The discovery of compound 5, a potent and selective inhibitor of TRPM4 with an additional chemical chaperone feature, revealed new opportunities for studying the role of TRPM4 in human diseases and developing clinical drug candidates.
Eco-friendly microwave synthesis of Mg(II) phenoxy carboxylic acid coordination compounds with specific motifs driven by multiple hydrogen bonding
Xu, Xiuling,Hu, Fan,Yan, Saisai,Lin, Jianguang,Li, Qing,Shuai, Qi
, p. 67610 - 67618 (2016/08/02)
Four novel Mg(ii) coordination compounds [Mg(CPA)2(H2O)4] 1, [Mg(H2O)6]·(MCPA)22, [Mg(DCPA)(H2O)5]·(DCPA) 3 and [Mg(TCPA)2(H2O)4]·2H2O 4 were designed by the strategy of hydrogen bonding driven self-assembly (HCPA = 2-chlorophenoxyacetic acid, HMCPA = 2-methyl-4-chlorophenoxyacetic acid, HDCPA = 2,3-dichlorophenoxyacetic acid and HTCPA = 2,4,6-trichlorophenoxyacetic acid). Single-crystal X-ray diffraction demonstrated that each coordination compound had its own specific motif driven by multiple hydrogen bonding: rectangle motif (compound 1), butterfly motif (compound 2), head and tail connected double heart-rectangle motif (compound 3) and alternative one side shared hexagon-rectangle motif (compound 4). The hydrogen bonding effects (O-H?Cl and O-H?O) on thermostability of the title compounds were well proved by TG analysis. The antibacterial activity of 1-4 has been explored, and all of them showed antibacterial efficiency against colibacillus at certain concentrations. The number of chlorides in the ligands seemed to affect the efficiency of the complexes while their position had no obvious effect. In addition, all the title compounds were evaluated for plant growth regulation by using the lettuce seedling growth bioassay. The results showed that these kinds of compounds had potential to serve as natural plant growth regulators because of their higher allelopathic activity. This research firstly applied the effective microwave method to synthesize Mg(ii) phenoxy carboxylic acid coordination compounds. The design strategy of hydrogen-bonding-driven self-assembly presented here gave a novel insight into the further structural prediction and biofunction achievement of Mg(ii) supramolecular assemblies.
