- Triaryl compound and preparation method and pharmaceutical application thereof
-
The invention discloses a triaryl compound as shown in a formula I which is described in the specification, physiologically acceptable salt, a preparation method of the compound, a pharmaceutical preparation containing the compound, and application of the
- -
-
Paragraph 0072; 0116-0118
(2020/12/14)
-
- Synthesis of 2,4-Disubstituted Imidazoles via Nucleophilic Catalysis
-
A convergent, microwave-assisted protocol for the synthesis of disubstituted NH-imidazoles via nucleophilic catalysis is described. The substituted imidazoles are accessed via the intramolecular addition of a variety of amidoxime substrates to activated a
- Camp, Jason E.,Dunsford, Jay J.,Gill, Duncan M.,Ngwerume, Simbarashe,Saunders, Alexandra R.,Shabalin, Dmitrii A.
-
supporting information
p. 797 - 800
(2020/05/19)
-
- Design, synthesis and biological evaluation of triaryl compounds as novel 20S proteasome inhibitors
-
Thirty novel triaryl compounds were designed and synthesized based on the known proteasome inhibitor PI-1840. Most of them showed significant inhibition against the β5c subunit of human 20S proteasome, and five of them exhibited IC50 values at the sub-micromolar level, which were comparable to or even more potent than PI-1840. The most active two (1c and 1d) showed IC50 values of 0.12 and 0.18 μM against the β5c subunit, respectively, while they displayed no obvious inhibition against the β2c, β1c and β5i subunits. Molecular docking provided informative clues for the subunit selectivity. The potent and subunit selective proteasome inhibitors identified herein represent new chemical templates for further molecular optimization.
- Yang, Yajun,Wang, Ke,Wu, Bo,Yang, Ying,Lai, Fangfang,Chen, Xiaoguang,Xiao, Zhiyan
-
-
- Novel 5-(quinuclidin-3-ylmethyl)-1,2,4-oxadiazoles to investigate the activation of the α7 nicotinic acetylcholine receptor subtype: Synthesis and electrophysiological evaluation
-
α7 nicotinic acetylcholine receptors (nAChRs) are relevant therapeutic targets for a variety of disorders including neurodegeneration, cognitive impairment, and inflammation. Although traditionally identified as an ionotropic receptor, the α7 subtype showed metabotropic-like functions, mainly linked to the modulation of immune responses. In the present work, we investigated the structure-activity relationships in a set of novel α7 ligands incorporating the 5-(quinuclidin-3-ylmethyl)-1,2,4-oxadiazole scaffold, i.e. derivatives 21a-34a and 21b-34b, aiming to identify the structural requirements able to preferentially trigger one of the two activation modes of this receptor subtype. The new compounds were characterized as partial and silent α7 nAChR agonists in electrophysiological assays, which allowed to assess the contribution of the different groups towards the final pharmacological profile. Overall, modifications of the selected structural backbone mainly afforded partial agonists, among them tertiary bases 27a-33a, whereas additional hydrogen-bond acceptor groups in permanently charged ligands, such as 29b and 31b, favored a silent desensitizing profile at the α7 nAChR.
- Quadri, Marta,Silnovi?, Almin,Matera, Carlo,Horenstein, Nicole A.,Stokes, Clare,De Amici, Marco,Papke, Roger L.,Dallanoce, Clelia
-
p. 207 - 228
(2018/10/23)
-
- Small Molecule Inhibition of MicroRNA miR-21 Rescues Chemosensitivity of Renal-Cell Carcinoma to Topotecan
-
Chemical probes of microRNA (miRNA) function are potential tools for understanding miRNA biology that also provide new approaches for discovering therapeutics for miRNA-associated diseases. MicroRNA-21 (miR-21) is an oncogenic miRNA that is overexpressed in most cancers and has been strongly associated with driving chemoresistance in cancers such as renal cell carcinoma (RCC). Using a cell-based luciferase reporter assay to screen small molecules, we identified a novel inhibitor of miR-21 function. Following structure-activity relationship studies, an optimized lead compound demonstrated cytotoxicity in several cancer cell lines. In a chemoresistant-RCC cell line, inhibition of miR-21 via small molecule treatment rescued the expression of tumor-suppressor proteins and sensitized cells to topotecan-induced apoptosis. This resulted in a >10-fold improvement in topotecan activity in cell viability and clonogenic assays. Overall, this work reports a novel small molecule inhibitor for perturbing miR-21 function and demonstrates an approach to enhancing the potency of chemotherapeutics specifically for cancers derived from oncomir addiction.
- Naro, Yuta,Ankenbruck, Nicholas,Thomas, Meryl,Tivon, Yaniv,Connelly, Colleen M.,Gardner, Laura,Deiters, Alexander
-
p. 5900 - 5909
(2018/08/04)
-
- COMPOSITIONS AND METHODS FOR CONTROL OF DISEASE
-
Compounds, compositions and methods for controlling root-originating diseases are described herein. The compounds include oxazoles, oxadiazoles and thiadiazoles. The compounds may be administered to plants, seeds, and/or soil.
- -
-
Paragraph 0315; 0339
(2018/08/30)
-
- COMPOSITIONS AND METHODS FOR IMPROVING AGRONOMIC CHARACTERISTICS OF PLANTS
-
Compounds, compositions and methods for improving one or more agronomic characteristics of desired crop plants are described herein. The compounds include oxazoles, oxadiazoles and thiadiazoles.
- -
-
Paragraph 0424
(2016/07/05)
-
- Discovery of highly potent triazole antifungal agents with piperidine-oxadiazole side chains
-
Due to increasing incidence and mortality of invasive fungal infections, discovery and development of new generations of antifungal agents represents a challenging task. On the basis of our previously reported triazole-benzyloxypiperidinyl lead compound, a series of novel triazole antifungal agents containing piperidine-oxadiazole side chains were rationally designed and synthesized. Most of the target compounds showed excellent inhibitory activity against clinically important fungal pathogens. In particular, compounds 6g (MIC = 0.031 μg mL-1) and 11b (MIC = 0.016 μg mL-1) were highly active against Candida albicans including fluconazole-resistant strains. Moreover, they showed inhibitory activity against hyphal formation with low toxicity, which were promising leads for further development. This journal is
- He, Xiaomeng,Jiang, Yan,Zhang, Yongqiang,Wu, Shanchao,Dong, Guoqiang,Liu, Na,Liu, Yang,Yao, Jianzhong,Miao, Zhenyuan,Wang, Yan,Zhang, Wannian,Sheng, Chunquan
-
p. 653 - 664
(2015/04/27)
-
- ALPHA-KETO HETEROCYCLES AS FAAH INHIBITORS
-
The invention provides a series of -alpha ketoheterocyclic compounds, for example, compounds of formula (I). The compounds can inhibit fatty acid amide hydrolase and can be useful for treatment of malconditions modulated by fatty acid amide hydrolase. The invention further provides methods of making compounds of formula (I), useful intermediates for the preparation of compounds of formula (I), and methods of using compounds of formula (I) and compositions thereof.
- -
-
Page/Page column 51
(2010/04/03)
-
- TRIAZOLE OXADIAZOLES DERIVATIVES
-
The invention relates to compounds of formula (I), wherein R1, R2, Ra, Rb, X have the meanings given in claim 1. The compounds are useful e.g. in the treatment of autoimmune disorders, such as multiple sclerosis.
- -
-
Page/Page column 114
(2009/07/25)
-
- Compostions and Methods for Controlling Nematodes
-
Compositions and processes for controlling nematodes are described herein, e.g., nematodes that infest plants or animals. The compounds include oxazoles, oxadiazoles and thiadiazoles.
- -
-
Page/Page column 41
(2009/03/07)
-
- Optimization of the central heterocycle of α-ketoheterocycle inhibitors of fatty acid amide hydrolase
-
The synthesis and evaluation of a refined series of α- ketoheterocycles based on the oxazole 2 (OL-135) incorporating systematic changes in the central heterocycle bearing a key set of added substituents are described. The nature of the central heterocycle, even within the systematic and minor perturbations explored herein, significantly influenced the inhibitor activity. 1,3,4-oxadiazoles and 1,2,4-oxadiazoles 9 > tetrazoles, the isomeric 1,2,4-oxadiazoles 10, 1,3,4-thiadiazoles > oxazoles including 2 > 1,2-diazines > thiazoles > 1,3,4-triazoles. Most evident in these trends is the observation that introduction of an additional heteroatom at position 4 (oxazole numbering, N > O > CH) substantially increases activity that may be attributed to a reduced destabilizing steric interaction at the FAAH active site. Added heterocycle substituents displaying well-defined trends may be utilized to enhance the inhibitor potency and, more significantly, to enhance the inhibitor selectivity. These trends, exemplified herein, emerge from both enhancements in the FAAH activity and simultaneous disruption of binding affinity for competitive off-target enzymes.
- Garfunkle, Joie,Ezzili, Cyrine,Rayl, Thomas J.,Hochstatter, Dustin G.,Hwang, Inkyu,Boger, Dale L.
-
supporting information; experimental part
p. 4392 - 4403
(2009/06/17)
-
- Potent and selective nonpeptidic inhibitors of procollagen C-proteinase
-
6-Cyclohexyl-N-hydroxy-3-(1,2,4-oxadiazol-5-yl)hexanamides were previously disclosed as inhibitors of procollagen C-proteinase (PCP) culminating in the identification of amide 1. Our objective was to discover a second inhibitor that would have improved affinity for PCP and to optimize properties for transepidermal delivery (TED) to intact skin. Further investigation of this template identified a number of potent PCP inhibitors (IC50 values of 2-6 nM) with improved TED flux. Sulfonamide 56 had excellent PCP enzyme activity when measured with a peptide substrate (Ki 8.7 nM) or with the endogenous substrate procollagen (IC50 3.4 nM) and demonstrates excellent selectivity over MMPs involved in wound healing (>10 000-fold). In the fibroplasia model, 56 inhibited deposition of insoluble collagen by 76 ± 2% at 10 μM and was very effective at penetrating human skin in vitro with a TED flux of 1.5 μg/cm2/h, which compares favorably with values for agents that are known to penetrate skin well in vivo. Based on this profile, 56 (UK-421,045) was selected as a candidate for further preclinical evaluation as a topically applied, dermal anti-scarring agent.
- Fish, Paul V.,Allan, Gillian A.,Bailey, Simon,Blagg, Julian,Butt, Richard,Collis, Michael G.,Greiling, Doris,James, Kim,Kendall, Jackie,McElroy, Andrew,McCleverty, Dawn,Reed, Charlotte,Webster, Robert,Whitlock, Gavin A.
-
p. 3442 - 3456
(2008/02/11)
-
- 2-(2-Thienyl)-5,6-dihydroxy-4-carboxypyrimidines as inhibitors of the hepatitis C virus NS5B polymerase: Discovery, SAR, modeling, and mutagenesis
-
Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed dihydroxypyrimidine carboxylates 2 as novel, reversible inhibitors of the HCV NS5B polymerase. This series was further developed into 5,6-dihydroxy-2-(2- thienyl)pyrimidine-4-carboxylic acids such as 34 (EC50 9.3 μM), which now show activity in the cell-based HCV replication assay. The structure-activity relationship of these inhibitors is discussed in the context of their physicochemical properties and of the polymerase crystal structure. We also report the results of mutagenesis experiments which support the proposed binding model, which involves pyrophosphate-like chelation of the active site Mg ions.
- Koch, Uwe,Attenni, Barbara,Malancona, Savina,Colarusso, Stefania,Conte, Immacolata,Di Filippo, Marcello,Harper, Steven,Pacini, Barbara,Giomini, Claudia,Thomas, Steven,Incitti, Ilario,Tomei, Licia,De Francesco, Raffaele,Altamura, Sergio,Matassa, Victor G.,Narjes, Frank
-
p. 1693 - 1705
(2007/10/03)
-
- Synthesis of 4,5-dihydro 1,2,4-oxadiazoles from N-unsubstituted amidoximes
-
4,5-Dihydro 1,2,4-oxadiazoles can be synthesized from aromatic and araliphatic amidoximes by cyclocondensation with aldehydes and ketones. Resulting heterocycles differ in substitution at C-3 and C-5 showing the scope of the simple reaction.
- Lessel,Herfs
-
-
- 1,2,4-Oxadiazole derivatives of phenylalanine: potential inhibitors of substance P endopeptidase
-
The synthesis and the biological activity of a series of benzyl or aryl substituted 1,2,4-oxadiazole derivatives of phenyl-alanine are described.A base-promoted intermolecular cyclization reaction was performed using racemic tert-butyloxycarbonyl protected phenylalanine methyl ester and an amidoxime.After deprotection of the amino function the compounds were evaluated for their affinity to rat brain NK1-receptors and as inhibitors of a specific substance P cleaving enzyme, substance P endopeptidase (SPE), isolated from human cerebrospinal fluid.The results indicate that several compounds are weak inhibitors of SPE.However, all compounds lacked appreciable NK1-receptor affinity.Keywords: 1,2,4-oxadiazoles / substance P endopeptidase / Phe-Phe mimetics / amide bioisostere / NK1-receptor affinity
- Borg, S.,Luthman, K.,Nyberg, F.,Terenius, L.,Hacksell, U.
-
p. 801 - 810
(2007/10/02)
-
- Analgesic and antiinflammatory properties of 2-benzofuran amidoximes
-
2-Benzofuran carboximidamide and various of its substituted derivatives have been tested for analgesic, anti-inflammatory and ulcerigeneous activity. For comparison, the same tests were performed with 2-naphto[2,1-b]furan carboximidamide, some 3-benzopyrancarboximidamides and 2-furan carboximidamide. Most 2-benzofurancarboximidamides show to have interesting analgesic properties. Some of them are also anti-inflammatories. 3-Methyl-5-bromo-2-benzofurancarboximidamide can be compared to aspirin and phenylbutazone as analgesic and anti-inflammatory respectively; no significant ulcerigeneous effect was noted for this compound.
- Riffaud,Dupont,Rene,Royer
-
p. 577 - 581
(2007/10/02)
-