- AROMATIC 2-NITROSULFONYL FLUORIDE ANTIBIOTICS AND METHODS OF USE THEREOF
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Aspects of the present disclosure include antibacterial aromatic sulfonyl fluoride agents. The subject aromatic sulfonyl fluoride agents have a pharmacophore that can provide for potent antibacterial activity. The subject agents are compounds including an
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Paragraph 0008
(2019/01/16)
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- Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 1: High-Throughput Screening and Preliminary Exploration
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Lysine specific demethylase 1 KDM1A (LSD1) regulates histone methylation and it is increasingly recognized as a potential therapeutic target in oncology. We report on a high-throughput screening campaign performed on KDM1A/CoREST, using a time-resolved fluorescence resonance energy transfer (TR-FRET) technology, to identify reversible inhibitors. The screening led to 115 hits for which we determined biochemical IC50, thus identifying four chemical series. After data analysis, we have prioritized the chemical series of N-phenyl-4H-thieno[3, 2-b]pyrrole-5-carboxamide for which we obtained X-ray structures of the most potent hit (compound 19, IC50 = 2.9 μM) in complex with the enzyme. Initial expansion of this chemical class, both modifying core structure and decorating benzamide moiety, was directed toward the definition of the moieties responsible for the interaction with the enzyme. Preliminary optimization led to compound 90, which inhibited the enzyme with a submicromolar IC50 (0.162 μM), capable of inhibiting the target in cells.
- Sartori, Luca,Mercurio, Ciro,Amigoni, Federica,Cappa, Anna,Fagá, Giovanni,Fattori, Raimondo,Legnaghi, Elena,Ciossani, Giuseppe,Mattevi, Andrea,Meroni, Giuseppe,Moretti, Loris,Cecatiello, Valentina,Pasqualato, Sebastiano,Romussi, Alessia,Thaler, Florian,Trifiró, Paolo,Villa, Manuela,Vultaggio, Stefania,Botrugno, Oronza A.,Dessanti, Paola,Minucci, Saverio,Zagarrí, Elisa,Carettoni, Daniele,Iuzzolino, Lucia,Varasi, Mario,Vianello, Paola
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supporting information
p. 1673 - 1692
(2017/03/17)
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- Heterocyclic-ring condensed benzothiazine compound
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The invention provides a novel heterocyclic ring condensed benzothiazine compound which is effective for prevention or remedy of disease, in which histamine, leukotriene and the like participate. The heterocyclic ring condensed benzothiazine compound of the present invention or a pharmacologically acceptable salt thereof is effective for prevention or remedy of disease, in which a chemical mediator, such as histamine, leukotriene and the like, participate, for example, asthma, allergic coryza, atopic dermatitis, hives, hay fever, gastrointestinal allergy, food allergy and the like. Further, the heterocyclic ring condensed benzothiazine compound of the present invention, its pharmacologically acceptable salt or hydrates thereof is represented by the following formula: In the formula, the ring Het represents an unsaturated heterocyclic ring; R1and R2are the same as or different from each other, and each represents halogen atom, a lower alkyl group that may be substituted with a halogen atom, a lower alkoxy group that may be substituted with a halogen atom, a lower alkyl lower alkoxy group, cyano group; D represents a lower alkylene group and the like that may have a substituent; Q represents, for example, the formula —NR20R2(in the formula, R20and R21are the same as or different from each other, and each represents hydrogen atom, a lower alkyl group that may be substituted with a halogen atom, an aryl group that may have a substituent, an arylalkyl group that may have a substituent, a heteroaryl group that may have a substituent or a heteroarylalkyl group that may have a substituent, or R20and R21may form a 3- to 8-membered ring along with the nitrogen atom to which they are bound); and x represents an integer of from 1 to 2.
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