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 backup program, we exploited structure-guided drug design to produce a new series of sulfone-containing derivatives, 2-sulfonylpiperazin 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 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.
Highlights
Macozinone (MCZ) is a tuberculosis (TB) drug candidate that targets the essential flavoenzyme DprE1, thereby blocking synthesis of the cell wall precursor decaprenyl phosphoarabinose (DPA) and provoking lysis of Mycobacterium tuberculosis
DprE1 inhibitors can be classified into two families according to their mode of action: some of them inhibit DprE1 irreversibly by forming a covalent adduct with cysteine 387 (C387) of DprE1, whereas others act as competitive noncovalent inhibitors [3]
When BTZ inhibitors bind to their target, DprE1, the sole bond formed is a covalent semimercaptal bond with the active-site cysteine residue, C387
Summary
Macozinone (MCZ) is a tuberculosis (TB) drug candidate that 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 backup program, we exploited structure-guided drug design to produce a new series of sulfone-containing derivatives, 2-sulfonylpiperazin 8-nitro 6-trifluoromethyl 1,3-benzothiazin-4-one, or sPBTZ. A common characteristic of the covalent DprE1 inhibitors is the presence of a nitro group on the molecule, which is essential for the mechanism of inhibition This nitro group is converted by DprE1 containing FADH2 into an extremely reactive nitroso group which targets the cysteine residue at position 387 (C387) in the active site of DprE1, to form a covalent. A class of noncovalent inhibitors, 2-carboxyquinoxalines, are active against BTZ-resistant M. tuberculosis strains with substitutions at C387 of DprE1 [14] Molecules from this family possess an essential 2-carboxylate moiety that forms key hydrogen bonds with the side chain of lysine 418 and the hydroxyl group of tyrosine 60 [18]. It can be hypothesized that a composite molecule between 2-carboxyquinoxalines and MCZ could overcome resistance issues and increase specificity to the target
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