Discovery of a Potent and Speci fi c M . tuberculosis Leucyl-tRNA Synthetase Inhibitor : ( S ) ‐ 3-( Aminomethyl )

There is an urgent need to develop new and safer antitubercular agents that possess a novel mode of action. We synthesized and evaluated a novel series of 3-aminomethyl 4-halogen benzoxaboroles as Mycobacterium tuberculosis (Mtb) leucyl-tRNA synthetase (LeuRS) inhibitors. A number of Mtb LeuRS inhibitors were identified that demonstrated good antitubercular activity with high selectivity over human mitochondrial and cytoplasmic LeuRS. Further evaluation of these Mtb LeuRS inhibitors by in vivo pharmacokinetics (PK) and murine tuberculosis (TB) efficacy models led to the discovery of GSK3036656 (abbreviated as GSK656). This molecule shows potent inhibition of Mtb LeuRS (IC50 = 0.20 μM) and in vitro antitubercular activity (Mtb H37Rv MIC = 0.08 μM). Additionally, it is highly selective for theMtb LeuRS enzyme with IC50 of >300 μM and 132 μM for human mitochondrial LeuRS and human cytoplasmic LeuRS, respectively. In addition, it exhibits remarkable PK profiles and efficacy against Mtb in mouse TB infection models with superior tolerability over initial leads. This compound has been progressed to clinical development for the treatment of tuberculosis. ■ INTRODUCTION Tuberculosis (TB) is a life-threatening infectious disease caused by the bacteria Mycobacterium tuberculosis (Mtb). The World Health Organization (WHO) estimates that one-third of the world’s population is infected with Mtb, resulting in 1.4 million deaths in 2015. In the same year, there were additional 0.4 million people infected with HIV who also died of TB disease. The current treatment for TB infection requires a combination therapy of four front-line drugs rifampin, isoniazid, pyrazinamide, and ethambutol for 6−9 months, often leading to significant side effects and poor patient compliance. In addition, emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) has rendered many front-line and second-line drugs ineffective. Furthermore, totally drug-resistant TB (TDR-TB) has recently emerged that is resistant to all clinical drugs. Therefore, there is an urgent need to develop new antitubercular agents that are effective against TB, which possess a novel mode of action that circumvents these resistances. Bedaquiline and delamanid have recently been approved by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA) to treat MDR-TB, representing the first new TB drugs in more than 40 years. Bedaquiline acts by the novel mechanism of mycobacterial adenosine 5′triphosphate (ATP) synthase inhibition, while delamanid is a nitroimidazole derivative that primarily inhibits synthesis of methoxymycolic and ketomycolic acid, which are components of the mycobacterial cell wall. However, bedaquiline has a boxed warning related to possible cardiac toxicity and delamanid (OPC-67683) induces QTc prolongation. In addition there is cross-resistance between clofazimine and bedaquiline as well as some of pre-existing resistance to delamanid. There has been an increased activity toward the discovery of new antitubercular agents. Other TB drug candidates that are in the clinical development include moxifloxacin, sutezolid, SQ109, and Q203 (Figure 1). We recently identified a series of 3-aminomethylbenzoxaboroles that target Mtb LeuRS (1−4, Figure 2). These Mtb LeuRS inhibitors require the boron atom for Mtb LeuRS activity since it forms a bidentate covalent adduct with the terminal nucleotide of tRNA, Ade76. The resulting covalent adduct traps the 3′ end of tRNA in the editing site in a nonproductive complex, inhibiting leucylation and thus protein synthesis. The amino group of the (S)-aminomethyl side chain at C-3 is critical for binding as it makes three hydrogen bonding interactions. An important finding from this work is that 4halogen atom (especially Cl and Br) significantly improves Mtb LeuRS activity, antitubercular activity against Mtb H37Rv, and selectivity against other bacteria. This effort led to the discovery Received: May 5, 2017 Published: September 27, 2017 Article