4659-45-4Relevant articles and documents
Ligand-Based Design of Allosteric Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) Inverse Agonists
Meijer, Femke A.,Doveston, Richard G.,De Vries, Rens M.J.M.,Vos, Ga?l M.,Vos, Alex A.A.,Leysen, Seppe,Scheepstra, Marcel,Ottmann, Christian,Milroy, Lech-Gustav,Brunsveld, Luc
, p. 241 - 259 (2020)
Retinoic acid receptor-related orphan receptor γt (RORγt) is a nuclear receptor associated with the pathogenesis of autoimmune diseases. Allosteric inhibition of RORγt is conceptually new, unique for this specific nuclear receptor, and offers advantages over traditional orthosteric inhibition. Here, we report a highly efficient in silico-guided approach that led to the discovery of novel allosteric RORγt inverse agonists with a distinct isoxazole chemotype. The the most potent compound, 25 (FM26), displayed submicromolar inhibition in a coactivator recruitment assay and effectively reduced IL-17a mRNA production in EL4 cells, a marker of RORγt activity. The projected allosteric mode of action of 25 was confirmed by biochemical experiments and cocrystallization with the RORγt ligand binding domain. The isoxazole compounds have promising pharmacokinetic properties comparable to other allosteric ligands but with a more diverse chemotype. The efficient ligand-based design approach adopted demonstrates its versatility in generating chemical diversity for allosteric targeting of RORγt.
Synthesis and structure-activity relationship studies of n-monosubstituted aroylthioureas as urease inhibitors
Dawalamu,Fang, Hai-Lian,Fu, Zi-Juan,Li, Fang,Li, Ke,Li, Wei-Yi,Liu, Li,Ni, Wei-Wei,Ouyang, Hui,Xiao, Zhu-Ping,Ye, Ya-Xi,Zhu, Hai-Liang,Zhu, Wen-Yan,Zou, Xia
, p. 1046 - 1059 (2021/11/30)
Background: Thiourea is a classical urease inhibitor which is usually used as a positive control, and many N,N'-disubstituted thioureas have been determined as urease inhibitors. However, due to steric hindrance, N,N'-disubstituted thiourea motif could not bind urease as thiourea. On the contrary, N-monosubstituted thiourea with a tiny thiourea motif could theoretically bind into the active pocket as thiourea. Objective: A series of N-monosubstituted aroylthioureas were designed and synthesized for evaluation as urease inhibitors. Methods: Urease inhibition was determined by the indophenol method and IC50 values were calculated using computerized linear regression analysis of quantal log dose-probit functions. The kinetic parameters were estimated via surface plasmon resonance (SPR) and by nonlinear regression analysis based on the mixed type inhibition model derived from Michaelis-Menten kinetics. Results: Compounds b2, b11, and b19 reversibly inhibited urease with a mixed mechanism, and showed excellent potency against both cell-free urease and urease in the intact cell, with IC50 values being 90-to 450-fold and 5-to 50-fold lower than the positive control acetohydroxamic acid, respectively. The most potent compound b11 showed an IC50 value of 0.060 ± 0.004μM against cell-free urease, which bound to urea binding site with a very low KD value (0.420±0.003nM) and a very long residence time (6.7 min). Compound b11 was also demonstrated to have very low cytotoxicity to mammalian cells. Conclusion: The results revealed that N-monosubstituted aroylthioureas bound to the active site of urease as expected, and represent a new class of urease inhibitors for the development of potential therapeutics against infections caused by urease-containing pathogens.
Synthesis of quinazolin-4(1 H)-ones via amination and annulation of amidines and benzamides
Hu, Fangpeng,Cui, Xinfeng,Ban, Zihui,Lu, Guoqiang,Luo, Nan,Huang, Guosheng
supporting information, p. 2356 - 2360 (2019/03/06)
Quinazolinones have broad applications in the biological, pharmaceutical and material fields. Studies on the synthesis of these compounds are therefore widely conducted. Herein, a novel and highly efficient copper-mediated tandem C(sp2)-H amination and annulation of benzamides and amidines for the synthesis of quinazolin-4(1H)-ones is proposed. This synthetic route can be useful for the construction of quinazolin-4(1H)-one frameworks.
Design, synthesis and evaluate in vitroantifungal activity of novel benzamide derivatives
Wang, Xuesong,Tang, Xiaorong
, p. 549 - 554 (2019/09/18)
Summary: A series of novel benzamide derivatives according to fluopicolide were designed and synthesized following the rule of combination carboxylic acid amides and amines derivatives together. The antifungal activity of the 15 new compounds were evaluated in vitroagainst five pathogenic fungi, including Sclerotinia sclerotiorum,Gibberella zeae, Rhizoctonia solani, Helminthosporium maydisand Botrytis cinerea. Almost all the structure have not been reported, except compounds 3, 5and 6. A surprising finding is that all the five tested fungi breed faster than negative controls when supplementary with compound 7-15, respectively.
N-ACYL AMINO ACID COMPOUNDS AND METHODS OF USE
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Paragraph 0430; 0431, (2018/03/28)
The invention relates to compounds of formula (I), or a salt thereof wherein R1, A, L, and R2 and n are as described herein. Compounds of formula (I) and pharmaceutical compositions thereof are ανβ1 integrin inhibitors that are useful for treating tissue specific fibrosis.
Investigation of novel pesticides with insecticidal and antifungal activities: Design, synthesis and SAR studies of benzoylpyrimidinylurea derivatives
Chen, Peiqi,Song, Xiangmin,Fan, Yongmei,Kong, Weihao,Zhang, Hao,Sun, Ranfeng
, (2018/09/10)
In order to find pesticides with insecticidal and antifungal activities, a series of novel benzoyl pyrimidinylurea derivatives were designed and synthesized. All target compounds were identified by 1H-NMR spectroscopy and HRMS. Insecticidal and antifungal activity of these compounds were evaluated and the structure-activity relationships (SAR) were clearly and comprehensively illustrated. Compound 7, with low toxicity to zebrafish (LC50 = 378.387 μg mL?1) showed 100% inhibition against mosquito (Culex pipiens pallens) at 0.25 μg mL?1. Both compounds 19 and 25 exhibited broad-spectrum fungicidal activity (>50% inhibitory activities against 13 phytopathogenic fungi), which were better than those of the commercial pesticide pyrimethanil (>50% inhibitory activities against eight phytopathogenic fungi). Furthermore, compounds 19 and 25 exhibited protective activity against Sclerotinia sclerotiorum on leaves of Brassica oleracea L. during in vivo experiments.
Noncovalent Interactions in Ir-Catalyzed C-H Activation: L-Shaped Ligand for Para-Selective Borylation of Aromatic Esters
Hoque, Md Emdadul,Bisht, Ranjana,Haldar, Chabush,Chattopadhyay, Buddhadeb
supporting information, p. 7745 - 7748 (2017/06/21)
An efficient strategy for the para-selective borylation of aromatic esters is described. For achieving high para-selectivity, a new catalytic system has been developed modifying the core structure of the bipyridine. It has been proposed that the L-shaped ligand is essential to recognize the functionality of the oxygen atom of the ester carbonyl group via noncovalent interaction, which provides an unprecedented controlling factor for para-selective C-H activation/borylation.
Design, synthesis and fungicidal activity of N-substituted benzoyl-1,2,3,4-tetrahydroquinolyl-1-carboxamide
Lei, Peng,Xu, Yan,Du, Juan,Yang, Xin-Ling,Yuan, Hui-Zhu,Xu, Gao-Fei,Ling, Yun
supporting information, p. 2544 - 2546 (2016/07/07)
To find a new lead compound with high biological activity, a series of N-substituted benzoyl-1,2,3,4-tetrahydroquinolyl-1-carboxamide were designed using linking active substructures method. The target compounds were synthesized from substituted benzoic acid by four steps and their structures were confirmed by 1H NMR, IR spectrum and elemental analysis. The in vitro bioassay results indicated that some target compounds exhibited excellent fungicidal activities, and the position of the substituents played an important role in fungicidal activities. Especially, compound 5n, exhibited better fungicidal activities than the commercial fungicide flutolanil against two tested fungi Valsa Mali and Sclerotinia sclerotiorum, with EC50 values of 3.44 and 2.63 mg/L, respectively. And it also displayed good in vivo fungicidal activity against S. sclerotiorum with the EC50 value of 29.52 mg/L.
Synthesis, antitumor activity and mechanism of action of novel 1,3-thiazole derivatives containing hydrazide–hydrazone and carboxamide moiety
He, Haifeng,Wang, Xiaoyan,Shi, Liqiao,Yin, Wenyan,Yang, Ziwen,He, Hongwu,Liang, Ying
supporting information, p. 3263 - 3270 (2016/07/12)
A series of novel 2,4,5-trisubstituted 1,3-thiazole derivatives containing hydrazide–hydrazine, and carboxamide moiety including 46 compounds T were synthesized, and evaluated for their antitumor activity in vitro against a panel of five human cancer cell lines. Eighteen title compounds T displayed higher inhibitory activity than that of 5-Fu against MCF-7, HepG2, BGC-823, Hela, and A549 cell lines. Especially, T1, T26 and T38 exhibit best cytotoxic activity with IC50values of 2.21?μg/mL, 1.67?μg/mL and 1.11?μg/mL, against MCF-7, BCG-823, and HepG2 cell lines, respectively. These results suggested that the combination of 1,3-thiazole, hydrazide–hydrazone, and carboxamide moiety was much favorable to cytotoxicity activity. Furthermore, the flow cytometry analysis revealed that compounds T1 and T38 could induce apoptosis in HepG2 cells, and it was confirmed T38 led the induction of cell apoptosis by S cell-cycle arrest.
Design and synthesis of N-benzoyl amino acid derivatives as DNA methylation inhibitors
Garella, Davide,Atlante, Sandra,Borretto, Emily,Cocco, Mattia,Giorgis, Marta,Costale, Annalisa,Stevanato, Livio,Miglio, Gianluca,Cencioni, Chiara,Fernández-de Gortari, Eli,Medina-Franco, José L.,Spallotta, Francesco,Gaetano, Carlo,Bertinaria, Massimo
, p. 664 - 676 (2016/10/25)
The inhibition of human DNA Methyl Transferases (DNMT) is a novel promising approach to address the epigenetic dysregulation of gene expression in different diseases. Inspired by the validated virtual screening hit NSC137546, a series of N-benzoyl amino acid analogues was synthesized and obtained compounds were assessed for their ability to inhibit DNMT-dependent DNA methylation in vitro. The biological screening allowed the definition of a set of preliminary structure–activity relationships and the identification of compounds promising for further development. Among the synthesized compounds, L-glutamic acid derivatives 22, 23, and 24 showed the highest ability to prevent DNA methylation in a total cell lysate. Compound 22 inhibited DNMT1 and DNMT3A activity in a concentration-dependent manner in the micromolar range. In addition, compound 22 proved to be stable in human serum and it was thus selected as a starting point for further biological studies.
