Structure-based drug design and characterization of sulfonyl-piperazine benzothiazinone inhibitors of DprE1 from Mycobacterium tuberculosis

Abstract

Macozinone (MCZ) is a tuberculosis (TB) drug candidate that specifically targets the essential flavoenzyme DprE1 thereby blocking synthesis of the cell wall precursor decaprenyl phosphoarabinose (DPA) and provoking lysis of Mycobacterium tuberculosis. As part of the MCZ back-up program we exploited structure-guided drug design to produce a new series of sulfone-containing derivatives, 2-sulphonylpiperazin 8-nitro 6-trifluoromethyl 1,3-benzothiazin-4-one, or sPBTZ. These compounds are less active than MCZ but have a better solubility profile and some derivatives display enhanced stability in microsomal assays. DprE1 was efficiently inhibited by sPBTZ and covalent adducts with the active site cysteine residue (C387) were formed. However, despite the H-bonding potential of the sulfone group no additional bonds were seen in the crystal structure of the sPBTZ-DprE1 complex with compound 11326127 as compared to MCZ. Compound 11626091, the most advanced sPBTZ, displayed good antitubercular activity in the murine model of chronic TB but was less effective than MCZ. Nonetheless, further testing of this MCZ backup compound is warranted as part of combination treatment with other TB drugs.

Identification of Mutations Associated With Macozinone-Resistant in Mycobacterium Tuberculosis

“…Macozinone (MCZ), previously known as PBTZ169, is currently undergoing Phase 1/2 clinical trails for the treatment of tuberculosis (8,9). MCZ had good bactericidal activity against multidrug-resistant tuberculosis strains and was effective against M.tb in replication phase (10)(11)(12). In the mouse infection model, MCZ showed excellent therapeutic effect.…”

Overcoming Mycobacterium tuberculosis through small molecule inhibitors to break down cell wall synthesis

“…Regarding the structure of BTZ043, Li et al . 89 used a scaffold-morphing strategy to design and synthesize three series of benzopyranone, benzoxazinone, and benzothiopyranone analogs. However, only the benzothiopyranone series exhibited good activity against MTB and had low cytotoxicity.…”

8-cyanobenzothiazinone analogs with potent antitubercular activity

“…The initially reported structure-activity relationships (SAR) demonstrated a requirement for a nitro group at C-8, a strongly electron-withdrawing group at C-6, no substituents at C-5 or C-7, a carbonyl at C-4 and sulfur at the first position [12][13][14]. The amino group at the C-2 position is the most tolerant to modification, consequently this position has been the most extensively explored to modulate potency and drug disposition properties [3,6,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. However, the 8-nitro group remains a potential liability for idiosyncratic toxicity, metabolism by abundant commensal bacterial nitroreductases, reductive activation by glutathione and other biological thiolates and observed drug resistance by mutation of Cys387 to Ser387 [34][35][36][37].…”