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. Nitro aromatic 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 nitro aromatic compounds synthesized by us and the others confirmed the postulated reactivity. The results indicate that nucleophiles such as thiolates, cyanide and hydride induce non-enzymatic 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 hypotheses for the mechanism of action of nitro aromatic 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.
Compounds containing boron atoms play increasingly important roles in the therapy and diagnosis of various diseases, particularly cancer. However, computational drug design of boron-containing therapeutics and diagnostics is hampered by the fact that many software packages used for this purpose lack parameters for all or part of the various types of boron atoms. In the present paper, we describe simple and efficient strategies to overcome this problem, which are based on the replacement of the boron atom types with carbon atom types. The developed methods were validated by docking closo-and nido-carboranyl antifolates into the active site of a human dihydrofolate reductase (hDHFR) using AutoDock, Glide, FlexX, and Surflex and comparing the obtained docking poses with the poses of their counterparts in the original hDHFR-carboranyl antifolate crystal structures. Under optimized conditions, AutoDock and Glide were equally good in docking of the closocarboranyl antifolates followed by Surflex and FlexX whereas Autodock, Glide, and Surflex proved to be comparably efficient in the docking of nido-carboranyl antifolates followed by FlexX. Differences in geometries and partial atom charges in the structures of the carboranyl antifolates resulting from different data sources and/or optimization methods did not impact the docking performances of AutoDock or Glide significantly. Scoring functions generated by all four programs were in accordance with experimental data.
Neutron capture therapy (NCT) is a binary radio-chemotherapeutic modality for the treatment of cancer. A major focus of NCT-related research is the development of novel tumor-selective agents that serve as the chemical component in NCT. Thymidine analogues substituted with a boron-containing carborane cluster at the N3 position, designated 3CTAs (3-carboranyl thymidine analogues), constitute one class of these new improved NCT agents. Their chemical, structural and biological properties are discussed in this Feature Article.
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.
Electron deficient nitroaromatic compounds such as BTZ043 and its closest congener, PBTZ169, and related agents are a promising new class of anti-TB compounds. Herein we report the design and syntheses of 1,3-benzothiazinone azide (BTZ-N 3 ) and related click chemistry products based on the molecular mode of activation of BTZ043. Our computational docking studies indicate that BTZ-N 3 binds in the essentially same pocket as that of BTZ043. Detailed biochemical studies with cell envelope enzyme fractions of Mycobacterium smegmatis combined with our model biochemical reactivity studies with nucleophiles indicated that, in contrast to BTZ043, the azide analogue may have a different mode of activation for anti-TB activity. Subsequent enzymatic studies with recombinant DprE1 from Mtb followed by MIC determination in NTB1 strain of Mtb (harboring Cys387Ser mutation in DprE1 and is BTZ043 resistant) unequivocally indicated that BTZ-N 3 is an effective reversible and noncovalent inhibitor of DprE1.
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