## 3 DprE1: The Hot TB Target of the Moment
### DprE1 Inhibitors, Which Are the Current Status and Future Perspectives  
Currently, at least 11 different scaffolds have been reported as effective DprE1 inhibitors, either covalent and noncovalent, showing different efficacy in vitro, ex vivo and in vivo [46]. It is noteworthy that the majority of these compounds have been identified through phenotypic screening, then subjected to optimization processes. The most representative compounds are reported in Table 1. \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Chemical Class** & **Compound** & **Structure** & _M. tuberculosis_ **MIC** & **Ref.** \\ \hline \multicolumn{5}{c}{Covalent inhibitors} \\ \hline \multirow{4}{*}{Benzothiazinones} & BTZ043 & \multirow{4}{*}{\(\begin{array}{c}\text{{NC}}\\ \text{{PBTZ169}}\end{array}\)} & \multirow{4}{*}{\(\begin{array}{c}\text{{NC}}\\ \text{{PBTZ169}}\end{array}\)} & \multirow{4}{*}{\(\begin{array}{c}\text{{NC}}\\ \text{{PBTZ169}}\end{array}\)} & \multirow{4}{*}{\(\begin{array}{c}\text{{NC}}\\ \text{{PBTZ169}}\end{array}\)} \\ \hline \multirow{4}{*}{Dinitrobenzamides} & DNB1 & \multirow{4}{*}{\(\begin{array}{c}\text{{NC}}\\ \text{{NC}}_{2}\end{array}\)} & \multirow{4}{*}{\(\begin{array}{c}\text{{NC}}\\ \text{{NC}}_{2}\end{array}\)} & \multirow{4}{*}{\(\begin{array}{c}\text{{NC}}\\ \text{{NC}}_{3}\end{array}\)} \\ \hline \multirow{4}{*}{Nitro-quinoxalines} & VI-9376 & \multirow{4}{*}{\(\begin{array}{c}\text{{NC}}\\ \text{{NC}}_{4}\end{array}\)} & \multirow{4}{*}{\(\begin{array}{c}\text{{NC}}\\ \text{{NC}}_{5}\end{array}\)} \\ \hline \multirow{4}{*}{Tiazoles} & \multirow{4}{*}{377790} & \multirow{4}{*}{\(\begin{array}{c}\text{{NC}}\\ \text{{NC}}_{6}\end{array}\)} & \multirow{4}{*}{\(\begin{array}{c}\text{{NC}}\\ \text{{NC}}_{7}\end{array}\)} \\ \hline \multicolumn{5}{c}{Noncovalent inhibitors} \\ \hline \multirow{4}{*}{Benzothiazoles} & TCA1 & \multirow{4}{*}{\(\begin{array}{c}\text{{NC}}\\ \text{{NC}}_{8}\end{array}\)} & \multirow{4}{*}{\(\begin{array}{c}\text{{NC}}\\ \text{{NC}}_{9}\end{array}\)} & \multirow{4}{*}{\(\begin{array}{c}\text{{NC}}\\ \text{{NC}}_{10}\end{array}\)} \\ \hline \multirow{4}{*}{Thiadiazoles} & GSK-710 & \multirow{4}{*}{\(\begin{array}{c}\text{{NC}}\\ \text{{NC}}_{11}\end{array}\)} & \multirow{4}{*}{\(\begin{array}{c}\text{{NC}}\\ \text{{NC}}_{12}\end{array}\)} \\ \hline \multirow{4}{*}{Carboxy-quinoxalines} & \multirow{4}{*}{Ty38c} & \multirow{4}{*}{\(\begin{array}{c}\text{{NC}}\\ \text{{NC}}_{13}\end{array}\)} & \multirow{4}{*}{\(\begin{array}{c}\text{{NC}}\\ \text{{NC}}_{14}\end{array}\)} & \multirow{4}{*}{\(\begin{array}{c}\text{{NC}}\\ \text{{NC}}_{15}\end{array}\)} \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Main covalent and not covalent DprE1 inhibitors showing antitubercular activity. The first DprE1 inhibitors identified is the BTZ043, belonging to the class of the benzothiazinones [30]. Moreover, nearly in the same period other classes of compounds, such as dinitrobenzamides, nitroquinoxaline and triazoles, have been described as covalent inhibitors [32; 33; 51]. As above reported, all these compounds possess a nitro group, that is converted to nitroos through the oxidation of the FADH\({}_{2}\) cofactor of DprE1, allowing the formation of a covalent bond with a cysteine residue. However, an alternative and similarly probable mechanism of formation of the nitroos group has been proposed. In this model, the thiol group of the cysteine is able to start the redox reaction which converts the nitro group into nitroos similarly to the [PERSON] reaction [65]. Despite BTZ043 was extremely potent against _M. tuberculosis_ with an MIC of 1 ng/mL (2.3 nM) [30], its great efficacy was not translated into a mouse model, probably due to its relatively high lipophilicity, and low pharmacokinetic properties. Several attempts were then done to improve this class of compounds, and in particular, a structure activity relationship (SAR) study of piperazine benzothiazinone derivatives afforded the PBTZ-169 [49].