Deuterated antimicrobial compounds
Inventors
Miller, Marvin J. • Krchnak, Viktor • Liu, Rui
Assignees
Publication Number
US-11731947-B2
Publication Date
2023-08-22
Expiration Date
2040-04-03
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Abstract
Substituted nitrobenzothiazinones (BTZs) are potent antituberculosis prodrugs that are reductively activated to produce nitroso moieties that form covalent adducts with a cysteine residue of decaprenylphosphoryl-β-D-ribose-2′-oxi-dase (DprE1) of Mycobacterium tuberculosis (Mtb). The resulting cell wall synthesis inhibition is lethal to Mtb, leading to consideration of development of BTZs for clinical use. The hydride-induced reduction of the nitroaromatic proceeds by reversible formation of the corresponding Meisenheimer complex. Herein we demonstrate that chemical reduction of BTZ043 with NaBD4 followed by reoxidation incorporates deuterium into the core nitro aromatic warhead. Subsequent reduction of the deuterated species is not affected, but, as expected, reoxidation is slowed by the deuterium isotope effect, thus prolonging the lifetime of the active nitroso oxidation state.
Core Innovation
The invention provides substituted nitrobenzothiazinones (BTZs), specifically deuterated at the ortho and/or para positions of the nitroaromatic core. These BTZs are potent antituberculosis prodrugs that, upon reductive activation, form nitroso intermediates which covalently modify the cysteine residue of the decaprenylphosphoryl-β-D-ribose-2′-oxidase (DprE1) enzyme in Mycobacterium tuberculosis (Mtb). The mechanism involves hydride-induced reduction to a Meisenheimer complex, followed by reoxidation to regenerate the active aromatic core.
The problem addressed by the invention relates to the worldwide challenge of tuberculosis (TB), particularly with rising incidences of multidrug-resistant, extensively-drug-resistant, and totally drug-resistant strains. Existing therapies are lengthily, prone to failure, and new drugs with novel mechanisms of action are urgently needed. Although deuteration is known to modulate metabolic and chemical stability, obtaining specifically deuterated drug analogs often requires complex and modified synthetic procedures compared to their parent counterparts.
This disclosure demonstrates a streamlined process for preparing deuterated BTZ compounds by chemical reduction of BTZ043 with NaBD4 followed by reoxidation, incorporating deuterium into methylene positions of the nitroaromatic warhead. The presence of deuterium slows the reoxidation due to the isotope effect, thereby extending the lifetime of the active nitroso oxidation state and potentially altering drug pharmacodynamics. The invention covers new compounds, their intermediates, synthesis methods, and use for treatment of microbial infections, particularly tuberculosis and leprosy in humans.
Claims Coverage
The patent contains four independent inventive features covering methods of synthesis, therapeutic treatment, and novel compounds.
Method for forming deuterated compounds of Formula IA, IB, or IC
This inventive feature covers a method involving: - Reacting a deuteride reducing agent with a compound of Formula IA (where R3 and R4 are hydrogen) to form a reduced intermediate. - Reacting the reduced intermediate with an oxidizing agent to form a compound of Formula IA with at least one deuterium at R3 or R4, or - Reacting the reduced intermediate with a protic reagent to form a compound of Formula IB or IC. The method results in deuterated nitrobenzothiazinone or nitrobenzamide derivatives and includes the possibility of forming azoxy dimers or salts thereof.
Method for treating a microbial infection with deuterated compounds
This inventive feature covers a method comprising: - Administering a therapeutically effective amount of a compound of Formula IA, IB, or IC to a subject in need thereof, - Where at least one of R3 or R4 is deuterium, - Thereby killing or inhibiting the growth of at least a portion of a plurality of microorganisms in the subject. This includes use for mycobacterial infections, such as tuberculosis or leprosy.
Deuterated compounds of Formula IA, IB, or IC
This inventive feature claims novel compounds of Formula IA, IB, or IC, or an azoxy dimer or salt thereof, where: - R1 is 2-(C1-C6)alkyl-1,4-dioxa-8-azaspiro[4.5]decan-8-yl or 4-((C3-C6)cycloalkyl methyl)piperazin-1-yl; - R2 is halo, cyano, —(C1-C3)alkyl, or —O(C1-C3)alkyl, where the alkyl or alkoxy has 2 to 7 halo substituents; - R3 and R4 are independently hydrogen, deuterium, halo, hydroxyl, cyano, —(C1-C6)alkyl, with at least one of R3 or R4 as deuterium; - R5 is hydrogen, deuterium, halo, hydroxyl, cyano, or —(C1-C6)alkyl.
Deuterium incorporation enhancement by reaction iteration
This inventive feature covers repeating the reduction/oxidation steps to further increase deuterium incorporation into the compounds, specifically by repeating: - Steps with a deuteride reducing agent and an oxidizing agent for Formula IA compounds, - Steps with a deuteride reducing agent and a protic agent for Formula IB or IC compounds.
The independent inventive features cover specific methods for preparing deuterated nitroaromatic antimicrobial agents, their use in treating microbial infections, the novel deuterated compounds themselves, and iterative processes for increasing deuterium incorporation.
Stated Advantages
The deuterium isotope effect slows reoxidation, prolonging the lifetime of the active nitroso oxidation state.
Substitution of C–H bonds by C–D bonds can significantly alter the metabolic profile of the compound, potentially improving pharmacodynamics, tolerability, and efficacy.
Facile and efficient synthesis allows for generation of specifically deuterated compositions without extensive modification of existing procedures.
The deuterated compounds retain potent antituberculosis activity, as confirmed by identical activity in whole cell assays to non-deuterated analogs.
Documented Applications
Treatment or prevention of tuberculosis in humans or other mammals.
Treatment or prevention of leprosy in humans or other mammals.
Treatment of non-tuberculosis mycobacterial infections where DprE1 enzyme with an essential cysteine residue is present.
Killing or inhibiting the growth of Mycobacterium tuberculosis, M. avium, M. leprae, or M. ulcerans in a subject.
Manufacture of medicaments for the treatment of microbial infections in mammals.
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