ACS Medicinal Chemistry Letters
Page 4 of 6
4. Wallis, R. S.; Maeurer, M.; Mwaba, P.; Chakaya, J.; Rustomjee,
dinitrobenzamides D5, 6, 7, 12 exhibit excellent in vitro inhibitory
activity against both drugꢀsensitive MTB strain H37Rv (MIC:
0.0625 ꢁg/mL) and drugꢀresistant clinical isolates (MIC < 0.016ꢀ
0.125 ꢁg/mL). Moreover, compound D6 displays acceptable safeꢀ
ty and better PK properties than PBTZ169, and it may serve as a
promising lead compound for further antitubercular drug discovꢀ
ery. Studies to determine the in vivo efficacy of D6 are currently
underway.
R.; Migliori, G. B.; Marais, B.; Schito, M.; Churchyard, G.; Swaminaꢀ
than, S.; Hoelscher, M.; Zumla, A., Tuberculosisꢀꢀadvances in develꢀ
opment of new drugs, treatment regimens, hostꢀdirected therapies, and
biomarkers. Lancet Infect. Dis. 2016, 16 (4), e34ꢀ46.
1
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3
4
5
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5. Nusrath Unissa, A.; Hanna, L. E.; Swaminathan, S., A Note on
Derivatives of Isoniazid, Rifampicin, and Pyrazinamide Showing
Activity Against Resistant Mycobacterium tuberculosis. Chem. Bio.
Drug Des. 2016, 87 (4), 537ꢀ50.
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ASSOCIATED CONTENT
Supporting Information
6. Kakkar, A. K.; Dahiya, N., Bedaquiline for the treatment of reꢀ
sistant tuberculosis: promises and pitfalls. Tuberculosis (Edinb) 2014,
94 (4), 357ꢀ62.
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7. Gler, M. T.; Skripconoka, V.; SanchezꢀGaravito, E.; Xiao, H.;
CabreraꢀRivero, J. L.; VargasꢀVasquez, D. E.; Gao, M.; Awad, M.;
Park, S. K.; Shim, T. S.; Suh, G. Y.; Danilovits, M.; Ogata, H.; Kurve,
A.; Chang, J.; Suzuki, K.; Tupasi, T.; Koh, W. J.; Seaworth, B.;
Geiter, L. J.; Wells, C. D., Delamanid for multidrugꢀresistant pulmoꢀ
nary tuberculosis. N Engl. J. Med. 2012, 366 (23), 2151ꢀ60.
Experimental procedures and analytical data of the synthesized
compounds were provided.
AUTHOR INFORMATION
Corresponding Author
8. Beena; Rawat, D. S., Antituberculosis drug research: a critical
overview. Med. Res. Rev. 2013, 33 (4), 693ꢀ764.
* lmllyx@126.com, 86ꢀ010ꢀ63030965 (M.L. Liu);
* luyu4876@hotmail.com (Y. Lu).
Author Contributions
9. Trefzer, C.; RengifoꢀGonzalez, M.; Hinner, M. J.; Schneider, P.;
Makarov, V.; Cole, S. T.; Johnsson, K., Benzothiazinones: Prodrugs
That Covalently Modify the DecaprenylphosphorylꢀbetaꢀDꢀribose 2 'ꢀ
epimerase DprE1 of Mycobacterium tuberculosis. J. Am. Chem. Soc.
2010, 132 (39), 13663ꢀ13665.
M.L.L. and Y.L. conceived and designed the project. L.L.H., K.L.
and Z.Y.T synthesized the compounds. B. W. evaluated the antiꢀ
zika virus activity. M. L.L., G.H.C., H.Y.G. and K.L. analyzed the
data and prepared the manuscript.The manuscript was written
through contributions of all authors. All authors have given apꢀ
proval to the final version of the manuscript.
10. Makarov, V.; Manina, G.; Mikusova, K.; Mollmann, U.;
Ryabova, O.; SaintꢀJoanis, B.; Dhar, N.; Pasca, M. R.; Buroni, S.;
Lucarelli, A. P.; Milano, A.; De Rossi, E.; Belanova, M.; Bobovska,
A.; Dianiskova, P.; Kordulakova, J.; Sala, C.; Fullam, E.; Schneider,
P.; McKinney, J. D.; Brodin, P.; Christophe, T.; Waddell, S.; Butcher,
P.; Albrethsen, J.; Rosenkrands, I.; Brosch, R.; Nandi, V.; Bharath, S.;
Gaonkar, S.; Shandil, R. K.; Balasubramanian, V.; Balganesh, T.;
Tyagi, S.; Grosset, J.; Riccardi, G.; Cole, S. T., Benzothiazinones Kill
Mycobacterium tuberculosis by Blocking Arabinan Synthesis. Science
2009, 324 (5928), 801ꢀ804.
‡These authors contributed equally.
Funding Sources
This work was financially supported by National Megaꢀproject
for
Innovative
Drugs
(2018ZX09721001ꢀ004ꢀ007,
2015ZX09102007ꢀ008,
2018ZX09711001ꢀ007ꢀ002,
11. Trefzer, C.; Skovierova, H.; Buroni, S.; Bobovska, A.; Nenci, S.;
Molteni, E.; Pojer, F.; Pasca, M. R.; Makarov, V.; Cole, S. T.; Ricꢀ
cardi, G.; Mikusova, K.; Johnsson, K., Benzothiazinones are suicide
2015ZX09102007ꢀ015, 2015ZX09304006ꢀ016), CAMS Initiative
for Innovative Medicine (CAMSꢀ2016ꢀI2Mꢀ1ꢀ010, CAMSꢀ2017ꢀ
I2Mꢀ1ꢀ011), PUMC Youth Fund (2017350011).
inhibitors
of
mycobacterial
decaprenylphosphorylꢀbetaꢀDꢀ
ribofuranose 2'ꢀoxidase DprE1. J. Am. Chem. Soc. 2012, 134 (2), 912ꢀ
5.
Notes
12. Christophe, T.; Jackson, M.; Jeon, H. K.; Fenistein, D.; Contreꢀ
rasꢀDominguez, M.; Kim, J.; Genovesio, A.; Carralot, J. P.; Ewann,
F.; Kim, E. H.; Lee, S. Y.; Kang, S.; Seo, M. J.; Park, E. J.;
Skovierova, H.; Pham, H.; Riccardi, G.; Nam, J. Y.; Marsollier, L.;
Kempf, M.; JolyꢀGuillou, M. L.; Oh, T.; Shin, W. K.; No, Z.; Nehrꢀ
bass, U.; Brosch, R.; Cole, S. T.; Brodin, P. High Content Screening
Identifies DecaprenylꢀPhosphoribose 2′Epimerase as a Target for
Intracellular Antimycobacterial Inhibitors. PLoS Pathog. 2009, 5,
e1000645.
The authors declare no competing financial interest.
ABBREVIATIONS
MTB, Mycobacterium tuberculosis; MDRꢀTB, multidrugꢀresistant
tuberculosis; XDRꢀTB, extensively drugꢀresistant tuberculosis;
WHO, World Health Organization; HIV, human immunodeficienꢀ
cy virus; BTZs, 8ꢀnitroꢀ6ꢀ(trifluoromethyl)ꢀ1,3ꢀbenzothiazinꢀ4ꢀ
ones; DprE1, Decaprenyl phosphorylꢀβꢀDꢀribose 2/ꢀepimerase;
DEAD, diethyl azodicarboxylate; DMSO, dimethylsulfoxide;
MIC, the minimum inhibitory concentration; MABA, Microplate
Alamar Blue Assay; Cmax, the maximum concentration; Tmax, the
time to maximum concentration; AUC0ꢀ∞, area under curve from
time zero to infinity; t1/2, the plasma elimination halfꢀlife;.
13. Trefzer, C.; RengifoꢀGonzalez, M.; Hinner, M. J.; Schneider, P.;
Makarov, V.; Cole, S. T.; Johnsson, K., Benzothiazinones: prodrugs
that covalently modify the decaprenylphosphorylꢀbetaꢀDꢀribose 2'ꢀ
epimerase DprE1 of Mycobacterium tuberculosis. J. Am. Chem. Soc.
2010, 132 (39), 13663ꢀ5.
14. Kappes, B.; Neumann, T.; Unger, E.; Dahse, H.ꢀM.; Mollmann,
U.; Schlegel, B. Use of 3,5ꢀdinitrobenzoate ester, 3,5ꢀ
dinitrobenzamide or 3,5ꢀdinitrophenyl ketone derivatives for therapy
and/or diagnosis of microbial infections, especially tuuberculosis or
malaria. Patent 2003, DE10158057.
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