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2-((3,5-Dinitrobenzyl)thio)quinazolinones : potent antimycobacterial agents activated by deazaflavin (F420)-dependent nitroreductase (Ddn)

Yanlin Jian, He Eun Forbes, Fabian Hulpia (UGent) , Martijn Risseeuw (UGent) , Guy Caljon, Hélène Munier-Lehmann, Helena I. M. Boshoff and Serge Van Calenbergh (UGent)
(2021) JOURNAL OF MEDICINAL CHEMISTRY. 64(1). p.440-457
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Abstract
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 F-420 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.
Keywords
Molecular Medicine, Drug Discovery, TUBERCULOSIS THYMIDYLATE KINASE, MYCOBACTERIUM-TUBERCULOSIS, RESISTANT TUBERCULOSIS, IDENTIFICATION, INHIBITORS, DERIVATIVES, DELAMANID, ASSAY

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MLA
Jian, Yanlin, et al. “2-((3,5-Dinitrobenzyl)Thio)Quinazolinones : Potent Antimycobacterial Agents Activated by Deazaflavin (F420)-Dependent Nitroreductase (Ddn).” JOURNAL OF MEDICINAL CHEMISTRY, vol. 64, no. 1, 2021, pp. 440–57, doi:10.1021/acs.jmedchem.0c01374.
APA
Jian, Y., Forbes, H. E., Hulpia, F., Risseeuw, M., Caljon, G., Munier-Lehmann, H., … Van Calenbergh, S. (2021). 2-((3,5-Dinitrobenzyl)thio)quinazolinones : potent antimycobacterial agents activated by deazaflavin (F420)-dependent nitroreductase (Ddn). JOURNAL OF MEDICINAL CHEMISTRY, 64(1), 440–457. https://doi.org/10.1021/acs.jmedchem.0c01374
Chicago author-date
Jian, Yanlin, He Eun Forbes, Fabian Hulpia, Martijn Risseeuw, Guy Caljon, Hélène Munier-Lehmann, Helena I. M. Boshoff, and Serge Van Calenbergh. 2021. “2-((3,5-Dinitrobenzyl)Thio)Quinazolinones : Potent Antimycobacterial Agents Activated by Deazaflavin (F420)-Dependent Nitroreductase (Ddn).” JOURNAL OF MEDICINAL CHEMISTRY 64 (1): 440–57. https://doi.org/10.1021/acs.jmedchem.0c01374.
Chicago author-date (all authors)
Jian, Yanlin, He Eun Forbes, Fabian Hulpia, Martijn Risseeuw, Guy Caljon, Hélène Munier-Lehmann, Helena I. M. Boshoff, and Serge Van Calenbergh. 2021. “2-((3,5-Dinitrobenzyl)Thio)Quinazolinones : Potent Antimycobacterial Agents Activated by Deazaflavin (F420)-Dependent Nitroreductase (Ddn).” JOURNAL OF MEDICINAL CHEMISTRY 64 (1): 440–457. doi:10.1021/acs.jmedchem.0c01374.
Vancouver
1.
Jian Y, Forbes HE, Hulpia F, Risseeuw M, Caljon G, Munier-Lehmann H, et al. 2-((3,5-Dinitrobenzyl)thio)quinazolinones : potent antimycobacterial agents activated by deazaflavin (F420)-dependent nitroreductase (Ddn). JOURNAL OF MEDICINAL CHEMISTRY. 2021;64(1):440–57.
IEEE
[1]
Y. Jian et al., “2-((3,5-Dinitrobenzyl)thio)quinazolinones : potent antimycobacterial agents activated by deazaflavin (F420)-dependent nitroreductase (Ddn),” JOURNAL OF MEDICINAL CHEMISTRY, vol. 64, no. 1, pp. 440–457, 2021.
@article{8685410,
  abstract     = {{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 F-420 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.}},
  author       = {{Jian, Yanlin and Forbes, He Eun and Hulpia, Fabian and Risseeuw, Martijn and Caljon, Guy and Munier-Lehmann, Hélène and Boshoff, Helena I. M. and Van Calenbergh, Serge}},
  issn         = {{0022-2623}},
  journal      = {{JOURNAL OF MEDICINAL CHEMISTRY}},
  keywords     = {{Molecular Medicine,Drug Discovery,TUBERCULOSIS THYMIDYLATE KINASE,MYCOBACTERIUM-TUBERCULOSIS,RESISTANT TUBERCULOSIS,IDENTIFICATION,INHIBITORS,DERIVATIVES,DELAMANID,ASSAY}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{440--457}},
  title        = {{2-((3,5-Dinitrobenzyl)thio)quinazolinones : potent antimycobacterial agents activated by deazaflavin (F420)-dependent nitroreductase (Ddn)}},
  url          = {{http://doi.org/10.1021/acs.jmedchem.0c01374}},
  volume       = {{64}},
  year         = {{2021}},
}
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