180146-67-2Relevant academic research and scientific papers
2-((3,5-Dinitrobenzyl)thio)quinazolinones: Potent Antimycobacterial Agents Activated by Deazaflavin (F420)-Dependent Nitroreductase (Ddn)
Jian, Yanlin,Forbes, He Eun,Hulpia, Fabian,Risseeuw, Martijn D. P.,Caljon, Guy,Munier-Lehmann, Hélène,Boshoff, Helena I. M.,Van Calenbergh, Serge
, p. 440 - 457 (2021/01/14)
Swapping the substituents in positions 2 and 4 of the previously synthesized but yet undisclosed 5-cyano-4-(methylthio)-2-arylpyrimidin-6-ones 4, ring closure, and further optimization led to the identification of the potent antitubercular 2-thio-substituted quinazolinone 26. Structure-activity relationship (SAR) studies indicated a crucial role for both meta-nitro substituents for antitubercular activity, while the introduction of polar substituents on the quinazolinone core allowed reduction of bovine serum albumin (BSA) binding (63c, 63d). While most of the tested quinazolinones exhibited no cytotoxicity against MRC-5, the most potent compound 26 was found to be mutagenic via the Ames test. This analogue exhibited moderate inhibitory potency against Mycobacterium tuberculosis thymidylate kinase, the target of the 3-cyanopyridones that lies at the basis of the current analogues, indicating that the whole-cell antimycobacterial activity of the present S-substituted thioquinazolinones is likely due to modulation of alternative or additional targets. Diminished antimycobacterial activity was observed against mutants affected in cofactor F420 biosynthesis (fbiC), cofactor reduction (fgd), or deazaflavin-dependent nitroreductase activity (rv3547), indicating that reductive activation of the 3,5-dinitrobenzyl analogues is key to antimycobacterial activity.
Development of 3,5-Dinitrophenyl-Containing 1,2,4-Triazoles and Their Trifluoromethyl Analogues as Highly Efficient Antitubercular Agents Inhibiting Decaprenylphosphoryl-β- d -ribofuranose 2′-Oxidase
Karabanovich, Galina,Du?ek, Jan,Savková, Karin,Pavli?, Oto,Pávková, Ivona,Korábe?ny, Jan,Ku?era, Tomá?,Ko?ová Vl?ková, Hana,Huszár, Stanislav,Konyariková, Zuzana,Kone?ná, Klára,Jand'Ourek, Ond?ej,Stola?íková, Ji?ina,Korduláková, Jana,Vávrová, Kate?ina,Pávek, Petr,Klime?ová, Věra,Hrabálek, Alexandr,Miku?ová, Katarína,Roh, Jaroslav
, p. 8115 - 8139 (2019/09/30)
We report herein the discovery of 3,5-dinitrophenyl 1,2,4-triazoles with excellent and selective antimycobacterial activities against Mycobacterium tuberculosis strains, including clinically isolated multidrug-resistant strains. Thorough structure-activity relationship studies of 3,5-dinitrophenyl-containing 1,2,4-triazoles and their trifluoromethyl analogues revealed the key role of the position of the 3,5-dinitrophenyl fragment in the antitubercular efficiency. Among the prepared compounds, the highest in vitro antimycobacterial activities against M. tuberculosis H37Rv and against seven clinically isolated multidrug-resistant strains of M. tuberculosis were found with S-substituted 4-alkyl-5-(3,5-dinitrophenyl)-4H-1,2,4-triazole-3-thiols and their 3-nitro-5-(trifluoromethyl)phenyl analogues. The minimum inhibitory concentrations of these compounds reached 0.03 μM, which is superior to all the current first-line anti-tuberculosis drugs. Furthermore, almost all compounds with excellent antimycobacterial activities exhibited very low in vitro cytotoxicities against two proliferating mammalian cell lines. The docking study indicated that these compounds acted as the inhibitors of decaprenylphosphoryl-β-d-ribofuranose 2′-oxidase enzyme, which was experimentally confirmed by two independent radiolabeling experiments.
Design and optimization of potent and orally bioavailable tetrahydronaphthalene raf inhibitors
Gould, Alexandra E.,Adams, Ruth,Adhikari, Sharmila,Aertgeerts, Kathleen,Afroze, Roushan,Blackburn, Christopher,Calderwood, Emily F.,Chau, Ryan,Chouitar, Jouhara,Duffey, Matthew O.,England, Dylan B.,Farrer, Cheryl,Forsyth, Nancy,Garcia, Khristofer,Gaulin, Jeffery,Greenspan, Paul D.,Guo, Ribo,Harrison, Sean J.,Huang, Shih-Chung,Iartchouk, Natalia,Janowik, Dave,Kim, Mi-Sook,Kulkarni, Bheemashankar,Langston, Steven P.,Liu, Jane X.,Ma, Li-Ting,Menon, Saurabh,Mizutani, Hirotake,Paske, Erin,Renou, Christelle C.,Rezaei, Mansoureh,Rowland, R. Scott,Sintchak, Michael D.,Smith, Michael D.,Stroud, Stephen G.,Tregay, Ming,Tian, Yuan,Veiby, Ole P.,Vos, Tricia J.,Vyskocil, Stepan,Williams, Juliet,Xu, Tianlin,Yang, Johnny J.,Yano, Jason,Zeng, Hongbo,Zhang, Dong Mei,Zhang, Qin,Galvin, Katherine M.
, p. 1836 - 1846 (2011/05/30)
Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.
NK-1 AND SEROTONIN TRANSPORTER INHIBITORS
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Page/Page column 64, (2010/11/28)
The invention encompasses compounds of Formula I, including pharmaceutically acceptable salts, their pharmaceutical compositions, and their use in treating disorders associated with an excess or imbalance of tachykinins or serotonin or both.
NOVEL PHARMACEUTICAL COMPOSITIONS COMPRISING AGONISTS OF THE THYROID RECEPTOR
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Page/Page column 48-49, (2010/02/14)
The invention provides compounds of formula I or a pharmaceutically acceptable ester, amide, solvate or salt thereof, including a salt of such an ester or amide, and a solvate of such an ester, amide or salt. The invention also provides the use of such compounds in the treatment or prophylaxis of a condition mediated by a thyroid receptor. Formula (I) wherein R1, R2, n, Y, Y', R3, R4, W and R5 are as defined in the specification.
THYROID RECEPTOR AGONISTS
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Page/Page column 66, (2010/02/14)
The invention provides compounds of formula (I) or a pharmaceutically acceptable ester, amide, solvate or salt thereof, including a salt of such an ester or amide, and a solvate of such an ester, amide or salt. The invention also provides the use of such compounds in the treatment or prophylaxis of a condition mediated by a thyroid receptor. Formula (I), wherein R1, R2, n, Y, Y', R3, R4, W and R5 are as defined in the specification.
Aniline derivatives possessing an inhibitory effect of nitric oxide synthase
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, (2008/06/13)
Compounds represented by the general formula (1): ? (where R1is SR6or NR7R8, where R6is typically an alkyl group having 1-6 carbon atoms, R7is a hydrogen atom, an alkyl group having 1-6 carbon atoms or a nitro group, and R8is a hydrogen atom or an alkyl group having 1-6 carbon atoms; R2and R3are each typically a hydrogen atom or an alkyl group having 1-6 carbon atoms; R4is a hydrogen atom, an alkyl group having 1-6 carbon atoms or an amidino group of which the amine portion may be substituted by an alkyl or nitro group; R5is a hydrogen atom or an alkyl group having 1-6 carbon atoms; Y1, Y2, Y3and Y4which may be the same or different are each typically a hydrogen atom, a halogen atom or an alkoxy group having 1-6 carbon atoms; n and m are each an integer of 0 or 1), or possible stereoisomers or optically active forms of the compounds or pharmaceutically acceptable salts thereof. The compounds possess a potent nitric oxide synthase inhibiting activity and are useful as therapeutics of cerebrovascular diseases.
