- 2-((3,5-Dinitrobenzyl)thio)quinazolinones: Potent Antimycobacterial Agents Activated by Deazaflavin (F420)-Dependent Nitroreductase (Ddn)
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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.
- Jian, Yanlin,Forbes, He Eun,Hulpia, Fabian,Risseeuw, Martijn D. P.,Caljon, Guy,Munier-Lehmann, Hélène,Boshoff, Helena I. M.,Van Calenbergh, Serge
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p. 440 - 457
(2021/01/14)
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- Dual copper- and photoredox-catalysed C(sp2)-C(sp3) coupling
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The use of copper catalysis with visible light photoredox catalysis in a cooperative fashion has recently emerged as a versatile means of developing new C-C bond forming reactions. In this work, dual copper and photoredox catalysis is exploited to effect C(sp2)-C(sp3) cross-couplings between aryl boronic acids and benzyl bromides.
- McLean, Euan B.,Gauchot, Vincent,Brunen, Sebastian,Burns, David J.,Lee, Ai-Lan
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supporting information
p. 4238 - 4241
(2019/04/30)
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- Electrosynthesis of dibenzonaphthyridine derivatives from 2,2-(2-nitrobenzyl)-2-substituted-acetonitriles
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An indirect electrochemical procedure involving an ex-cell two-phase process is proposed to produce dibenzonaphthyridine derivatives from 2,2-(2-nitrobenzyl)-2-substituted-acetonitriles in dichloromethane. The selective reduction of both nitro groups into amino groups using Cp2Ti+ in aqueous acidic medium avoids a cyclization of hydroxylamine intermediates as observed by direct electrolysis.
- Jan, Thierry,Dupas, Béatrice,Floner, Didier,Moinet, Claude
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p. 5949 - 5952
(2007/10/03)
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