| Reference | 1. Angew Chem Int Ed Engl. 2017 Feb 13;56(8):2187-2191. doi: 10.1002/anie.201609737. Epub 2017 Jan 18.<br />
In Vivo Dearomatization of the Potent Antituberculosis Agent BTZ043 via Meisenheimer Complex Formation.<br />
Kloss F(1)(2), Krchnak V(3)(4), Krchnakova A(3), Schieferdecker S(1)(5)(2), Dreisbach J(6)(7), Krone V(7), Möllmann U(1), Hoelscher M(6)(7), Miller MJ(3).<br />
Author information:<br />
(1)Transfer Group Antiinfectives, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745, Jena, Germany. (2)InfectControl 2020, Beutenbergstrasse 11a, 07745, Jena, Germany. (3)Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46635, USA. (4)Department of Organic Chemistry, Faculty of Science, Palacký University, 17. Listopadu 12, 771 46, Olomouc, Czech Republic. (5)Department of Biomolecular Chemistry, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745, Jena, Germany. (6)Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Leopoldstrasse 5, 80802, Munich, Germany. (7)German Center for Infection Research (DZIF) partner site Munich, Germany.<br />
Nitrobenzothiazinones are among the most potent antituberculosis agents. Herein, we disclose an unprecedented in vivo reduction process that affords Meisenheimer complexes of the clinical candidates BTZ043 and PBTZ169. The reduction is reversible, occurs in all mammalian species investigated, has a profound influence on the in vivo ADME characteristics, and has considerable implications for the design and implementation of clinical studies. The reduction was confirmed by chemical studies that enabled the complete characterization of the Meisenheimer complex and its subsequent chemistry. Combination of the in vivo and chemical studies with LC-MS characterization and assay development also provides a basis for rational lead optimization of this very promising class of antituberculosis agents.<br />
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2. ACS Med Chem Lett. 2014 Nov 29;6(2):128-33. doi: 10.1021/ml5003458. eCollection 2015 Feb 12.<br />
Syntheses and Antituberculosis Activity of 1,3-Benzothiazinone Sulfoxide and Sulfone Derived from BTZ043.<br />
Tiwari R(1), Miller PA(1), Cho S(2), Franzblau SG(2), Miller MJ(1).<br />
Author information:<br />
(1)Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States. (2)Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago , 833 South Wood Street, Chicago, Illinois 60612, United States.<br />
The discovery of 1,3-benzothiazin-4-ones (BTZs), especially BTZ043 and PBTZ-169 as potent agents for the treatment of tuberculosis, prompted intensive research related to development of potential antituberculosis agents based on electron deficient nitroaromatic scaffolds. Herein we report the syntheses, computational and NMR studies and anti-TB activity of oxidation products, 1,3-benzothiazinone sulfoxide (BTZ-SO) and 1,3-benzothiazinone sulfone (BTZ-SO2) derived from BTZ043. The combined computational and NMR work revealed differences in the total charge densities and molecular shapes of the oxidation products. While docking studies still suggested similar interactions and binding patterns for both products with the target DprE1 enzyme, antituberculosis assays indicated remarkable differences in their activity. Interestingly, BTZ-SO possesses potent activity against nonpathogenic and pathogenic mycobacterial strains, but BTZ-SO2 is only weakly active.<br />
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3. J Am Chem Soc. 2013 Mar 6;135(9):3539-49. doi: 10.1021/ja311058q. Epub 2013 Feb 25.<br />
Thiolates chemically induce redox activation of BTZ043 and related potent nitroaromatic anti-tuberculosis agents.<br />
Tiwari R(1), Moraski GC, Krchňák V, Miller PA, Colon-Martinez M, Herrero E, Oliver AG, Miller MJ.<br />
Author information:<br />
(1)Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.<br />
The development of multidrug resistant (MDR) and extensively drug resistant (XDR) forms of tuberculosis (TB) has stimulated research efforts globally to expand the new drug pipeline. Nitroaromatic compounds, including 1,3-benzothiazin-4-ones (BTZs) and related agents, are a promising new class for the treatment of TB. Research has shown that the nitroso intermediates of BTZs that are generated in vivo cause suicide inhibition of decaprenylphosphoryl-β-D-ribose 2' oxidase (DprE1), which is responsible for cell wall arabinogalactan biosynthesis. We have designed and synthesized novel anti-TB agents inspired from BTZs and other nitroaromatic compounds. Computational studies indicated that the unsubstituted aromatic carbons of BTZ043 and related nitroaromatic compounds are the most electron-deficient and might be prone to nucleophilic attack. Our chemical studies on BTZ043 and the additional nitroaromatic compounds synthesized by us and others confirmed the postulated reactivity. The results indicate that nucleophiles such as thiolates, cyanide, and hydride induce nonenzymatic reduction of the nitro groups present in these compounds to the corresponding nitroso intermediates by addition at the unsubstituted electron-deficient aromatic carbon present in these compounds. Furthermore, we demonstrate here that these compounds are good candidates for the classical von Richter reaction. These chemical studies offer an alternate hypothesis for the mechanism of action of nitroaromatic anti-TB agents, in that the cysteine thiol(ate) or a hydride source at the active site of DprE1 may trigger the reduction of the nitro groups in a manner similar to the von Richter reaction to the nitroso intermediates, to initiate the inhibition of DprE1.<br />
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4. Antimicrob Agents Chemother. 2012 Nov;56(11):5790-3. doi: 10.1128/AAC.01476-12. Epub 2012 Aug 27.<br />
In vitro combination studies of benzothiazinone lead compound BTZ043 against Mycobacterium tuberculosis.<br />
Lechartier B(1), Hartkoorn RC, Cole ST.<br />
Author information:<br />
(1)Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.<br />
Benzothiazinones (BTZ) are a new class of drug candidates to combat tuberculosis that inhibit decaprenyl-phosphoribose epimerase (DprE1), an essential enzyme involved in arabinan biosynthesis. Using the checkerboard method and cell viability assays, we have studied the interaction profiles of BTZ043, the current lead compound, with several antituberculosis drugs or drug candidates against Mycobacterium tuberculosis strain H37Rv, namely, rifampin, isoniazid, ethambutol, TMC207, PA-824, moxifloxacin, meropenem with or without clavulanate, and SQ-109. No antagonism was found between BTZ043 and the tested compounds, and most of the interactions were purely additive. Data from two different approaches clearly indicate that BTZ043 acts synergistically with TMC207, with a fractional inhibitory concentration index of 0.5. TMC207 at a quarter of the MIC (20 ng/ml) used in combination with BTZ043 (1/4 MIC, 0.375 ng/ml) had a stronger bactericidal effect on M. tuberculosis than TMC207 alone at a concentration of 80 ng/ml. This synergy was not observed when the combination was tested on a BTZ-resistant M. tuberculosis mutant, suggesting that DprE1 inhibition is the basis for the interaction. This finding excludes the possibility of synergy occurring through an off-target mechanism. We therefore hypothesize that sub-MICs of BTZ043 weaken the bacterial cell wall and allow improved penetration of TMC207 to its target. Synergy between two new antimycobacterial compounds, such as TMC207 and BTZ043, with novel targets, offers an attractive foundation for a new tuberculosis regimen.<br />
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