Thiolates Chemically Induce Redox Activation of BTZ043 and Related Potent Nitroaromatic Anti-Tuberculosis Agents

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.