Antitubercular Nitroimidazoles Revisited: Synthesis and Activity of the Authentic 3-Nitro Isomer of Pretomanid.
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Thompson AM, Bonnet M, Lee HH, Franzblau SG, Wan B, Wong GS, Cooper CB, Denny WA
Antitubercular Nitroimidazoles Revisited: Synthesis and Activity of the Authentic 3-Nitro Isomer of Pretomanid.
ACS Med Chem Lett. 2017 Nov 13;8(12):1275-1280. doi: 10.1021/acsmedchemlett.7b00356. eCollection 2017 Dec 14.
- PubMed ID
- 29259747 [ View in PubMed]
- Abstract
A published study of structural features associated with the aerobic and anaerobic activities of 4- and 5-nitroimidazoles had found that the 3-nitro isomer of pretomanid, 8, displayed interesting potencies, including against nitroreductase mutant Mycobacterium tuberculosis. However, recent nuclear magnetic resonance analyses of two trace byproducts, isolated from early process optimization studies toward a large-scale synthesis of pretomanid, raised structural assignment queries, particularly for 8, stimulating further investigation. Following our discovery that the reported compound was a 6-nitroimidazooxazole derivative, we developed a de novo synthesis of authentic 8 via nitration of the chiral des-nitro imidazooxazine alcohol 26 in trifluoroacetic or acetic anhydride, and verified its identity through an X-ray crystal structure. Unfortunately, 8 displayed no antitubercular activity (MICs > 128 muM), whereas the second byproduct (3'-methyl pretomanid) was eight-fold more potent than pretomanid in the aerobic assay. These findings further clarify target specificities for bicyclic nitroimidazoles, which may become important in the event of any future clinical resistance.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Pretomanid Deazaflavin-dependent nitroreductase Protein Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) UnknownSubstrateDetails - Drug Reactions
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