61535-46-4Relevant academic research and scientific papers
Synthesis, structure-activity relationships, cocrystallization and cellular characterization of novel smHDAC8 inhibitors for the treatment of schistosomiasis
Darwish, Salma,Erdmann, Frank,Ghazy, Ehab,Heimburg, Tino,Jung, Manfred,Lancelot, Julien,Pierce, Raymond,Robaa, Dina,Romier, Christophe,Schmidt, Matthias,Schmidtkunz, Karin,Shaik, Tajith B.,Simoben, Conrad V.,Sippl, Wolfgang,Truhn, Anne,Zeyen, Patrik
, (2021/08/17)
Schistosomiasis is a major neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy consists of mass treatment with the only available drug, praziquantel. In this study, we chemically optimized our previously reported benzhydroxamate-based inhibitors of Schistosoma mansoni histone deacetylase 8 (smHDAC8). Crystallographic analysis provided insights into the inhibition mode of smHDAC8 activity by the highly potent inhibitor 5o. Structure-based optimization of the novel inhibitors was carried out using the available crystal structures as well as docking studies on smHDAC8. The compounds were evaluated in screens for inhibitory activity against schistosome and human HDACs (hHDAC). The in vitro and docking results were used for detailed structure activity relationships. The synthesized compounds were further investigated for their lethality against the schistosome larval stage using a fluorescence-based assay. The most promising inhibitor 5o showed significant dose-dependent killing of the schistosome larvae and markedly impaired egg laying of adult worm pairs maintained in culture.
Hydrophobicity-oriented drug design (HODD) of new human 4-hydroxyphenylpyruvate dioxygenase inhibitors
Ndikuryayo, Ferdinand,Kang, Wei-Ming,Wu, Feng-Xu,Yang, Wen-Chao,Yang, Guang-Fu
, p. 22 - 31 (2019/01/26)
Involved in the tyrosine degradation pathway, 4-hydroxyphenylpyruvate dioxygenase (HPPD) is an important target for treating type I tyrosinemia. To discover novel HPPD inhibitors, we proposed a hydrophobicity-oriented drug design (HODD) strategy based on the interactions between HPPD and the commercial drug NTBC. Most of the new compounds showed improved activity, compound d23 being the most active candidate (IC50 = 0.047 μM) with about 2-fold more potent than NTBC (IC50 = 0.085 μM). Therefore, compound d23 is a potential drug candidate to treat type I tyrosinemia.
APOPTOSIS SIGNAL-REGULATING KINASE 1 (ASK 1) INHIBITOR COMPOUNDS
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Paragraph 00273, (2019/06/09)
Described herein are ASK1 inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with ASK1
Metathesis-active ligands enable a catalytic functional group metathesis between aroyl chlorides and aryl iodides
Lee, Yong Ho,Morandi, Bill
, p. 1016 - 1022 (2018/09/06)
Current methods for functional group interconversion have, for the most part, relied on relatively strong driving forces which often require highly reactive reagents to generate irreversibly a desired product in high yield and selectivity. These approaches generally prevent the use of the same catalytic strategy to perform the reverse reaction. Here we describe a catalytic functional group metathesis approach to interconvert, under CO-free conditions, two synthetically important classes of electrophiles that are often employed in the preparation of pharmaceuticals and agrochemicals—aroyl chlorides (ArCOCl) and aryl iodides (ArI). Our reaction design relies on the implementation of a key reversible ligand C–P bond cleavage event, which enables a non-innocent, metathesis-active phosphine ligand to mediate a rapid aryl group transfer between the two different electrophiles. Beyond enabling a practical and safer approach to the interconversion of ArCOCl and ArI, this type of ligand non-innocence provides a blueprint for the development of a broad range of functional group metathesis reactions employing synthetically relevant aryl electrophiles.
Substitution of terminal amide with 1H-1,2,3-triazole: Identification of unexpected class of potent antibacterial agents
Bi, Fangchao,Ji, Shengli,Venter, Henrietta,Liu, Jingru,Semple, Susan J.,Ma, Shutao
supporting information, p. 884 - 891 (2018/02/15)
3-Methoxybenzamide (3-MBA) derivatives have been identified as novel class of potent antibacterial agents targeting the bacterial cell division protein FtsZ. As one of isosteres for the amide group, 1,2,3-triazole can mimic the topological and electronic features of the amide, which has gained increasing attention in drug discovery. Based on these considerations, we prepared a series of 1H-1,2,3-triazole-containing 3-MBA analogues via isosteric replacement of the terminal amide with triazole, which had increased antibacterial activity. This study demonstrated the possibility of developing the 1H-1,2,3-triazole group as a terminal amide-mimetic element which was capable of both keeping and modulating amide-related bioactivity. Surprisingly, a different action mode of these new 1H-1,2,3-triazole-containing analogues was observed, which could open new opportunities for the development of antibacterial agents.
APOPTOSIS SIGNAL-REGULATING KINASE 1 (ASK 1) INHIBITOR COMPOUNDS
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Paragraph 00270-00271, (2018/10/25)
Described herein are ASK1 inhibitors, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with ASK1 activity.
Design, synthesis, and biological evaluation of oxazolidone derivatives as highly potent N-acylethanolamine acid amidase (NAAA) inhibitors
Ren, Jie,Li, Yuhang,Ke, Hongwei,Li, Yanting,Yang, Longhe,Yu, Helin,Huang, Rui,Lu, Canzhong,Qiu, Yan
, p. 12455 - 12463 (2017/03/11)
N-Acylethanolamine-hydrolyzing acid amidase (NAAA) is a lysosomal enzyme that catalyzes the hydrolysis of endogenous fatty acid ethanolamides (FAEs), such as N-palmitoylethanolamide (PEA). PEA exhibits anti-inflammatory and analgesic activities by engaging peroxisome proliferator-activated receptor α (PPAR-α). Preventing PEA degradation by inhibition of NAAA has been proposed as a novel strategy for the treatment of inflammation and pain. In the present study, we reported the discovery of the oxazolidone derivative as a novel scaffold for NAAA inhibitors, and studied the structure-activity relationship (SAR) by modification of the side chain and terminal lipophilic substituents. The results showed that the link chain length of C5, straight and saturated linkages were the preferred shape patterns for NAAA inhibition. Several nanomolar NAAA inhibitors were described, including 2f, 3h, 3i and 3j with IC50 values of 270 nM, 150 nM, 100 nM and 190 nM, respectively. Enzymatic degradation studies suggested that 2f inhibited NAAA in a selective, noncompetitive and reversible pattern. Moreover, 2f showed high anti-inflammatory and analgesic activities after systemic and oral administration.
Chelation-Assisted Nickel-Catalyzed Oxidative Annulation via Double C-H Activation/Alkyne Insertion Reaction
Misal Castro, Luis C.,Obata, Atsushi,Aihara, Yoshinori,Chatani, Naoto
supporting information, p. 1362 - 1367 (2016/01/25)
A nickel/NHC system for regioselective oxidative annulation by double C-H bond activation and concomitant alkyne insertion is described. The catalytic reaction requires a bidentate directing group, such as an 8-aminoquinoline, embedded in the substrate. Various 5,6,7,8-tetrasubstituted-N-(quinolin-8-yl)-1-naphthamides can be prepared as well as phenanthrene and benzo[h]quinoline amide derivatives. Diarylalkynes, dialkylalkynes, and arylalkylalkynes can be used in the system. A Ni0/NiII catalytic cycle is proposed as the main catalytic cycle. The alkyne plays a double role as a two-component coupling partner and as a hydrogen acceptor. In two shakes: Oxidative annulation by a double C-H activation/alkyne insertion reaction was achieved by a nickel/NHC system. A Ni0/NiII catalytic cycle is proposed as the main catalytic cycle. The alkyne plays a double role as a two-component coupling partner and as a hydrogen acceptor.
Regulating competing supramolecular interactions using ligand concentration
Teunissen, Abraham J. P.,Paffen, Tim F. E.,Ercolani, Gianfranco,De Greef, Tom F. A.,Meijer
supporting information, p. 6852 - 6860 (2016/06/14)
The complexity of biomolecular systems inevitably leads to a degree of competition between the noncovalent interactions involved. However, the outcome of biological processes is generally very well-defined often due to the competition of these interaction
NOVEL COMPOUNDS AND USES THEREOF
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Paragraph 00607, (2015/01/06)
The present invention provides novel compounds of any one of Formulae (I)-(IV), and pharmaceutical compositions thereof. Also provided are particles (e.g., nanoparticles) comprising compounds of any one of Formulae (I)-(IV) and pharmaceutical compositions
