4.2.5. TBA-7371

*Discovery.* TBA-7371 was developed in collaboration between Astra Zeneca and the TB Global Alliance. TBA-7371 is a derivative of 1,4-azaindoles developed through scaffold morphing of an imidazopyridine compound with good MIC but low minimum bactericidal activity (MBC) against *M. tuberculosis* [234]. SAR on the hit azaindole compound led to TBA-7371.

*Activity.* TBA-7371 is bactericidal against *M. tuberculosis*, with a MIC ranging from 0.78 to 3.12 μm against drug-susceptible and drug-resistant clinical isolates of *M. tuberculosis* [235]. Solubility of TBA-7371 is 170 μm. TBA-7371 does not exhibit toxicity in THP1 cell line up to concentration of 0.1 mM [235].

*Mode of action.* TBA-7371 inhibits DprE1 with an IC50 of 10–30 nm but, unlike BTZ043 and PBTZ169, TBA-7371 is a non-covalent inhibitor of DprE1 [234].

*Resistance.* Resistance to TBA-7371 was observed in strains overexpressing *M. tuberculosis dprE1* or carrying the mutation Y314H in *dprE1*, but not in strains with a mutated Cys387 in *dprE1* [234].

*Clinical trial.* TBA-7371 is in phase I clinical trial (NCT03199339) for safety, tolerability and pharmacokinetic studies in healthy adults. No results have been posted.

DprE1 is a successful drug target. Since the discovery of BTZ043 and its target DprE1 [225], numerous groups have uncovered novel molecules that target DprE1. DprE1 inhibitors can be divided into two groups depending on whether or not they bind covalently to DprE1. The presence of the nitro group is a requirement for the covalent binding to the Cys387 amino acid of DprE1. Among the covalent inhibitors are benzothiazinethione [236], dinitrobenzamides [237], nitroquinoxalines [238] and nitroimidazoles [239]. Several non-covalent DprE1 inhibitors have been identified with various chemical structures: azaindoles [234], benzothiazoles [240], pyrazolopyridones [241], aminoquinolone piperidine amides [242], carboxyquinoxalines [243], pyrrole-benzothiazinones [244], pyridobenzimidazole [245], sulfonylpiperazin-benzothiazinones [246] and piperidinopyrimidines [247]. These compounds inhibit DprE1 through electrostatic or hydrophobic interactions with different sites of DprE1. Most of these compounds have low MICs (in the nM range), are active against MDR and XDR TB as well as in a mouse model of *M. tuberculosis* infection. Considering the promiscuity of the DprE1 target, better DprE1 inhibitors might still be discovered to improve TB treatment.
