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New Insight into Dearomatization and Decarbonylation of Antitubercular 4 H ‐Benzo[ e ][1,3]thiazinones: Stable 5 H ‐ and 7 H ‐Benzo[ e ][1,3]thiazines
Author(s) -
Richter Adrian,
Seidel Rüdiger W.,
Graf Jürgen,
Goddard Richard,
Lehmann Christoph,
Schlegel Tom,
Khater Nour,
Imming Peter
Publication year - 2022
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202200021
Subject(s) - chemistry , antimycobacterial , decarbonylation , stereochemistry , reagent , nitro , medicinal chemistry , mycobacterium tuberculosis , organic chemistry , tuberculosis , medicine , alkyl , pathology , catalysis
8‐Nitro‐4 H ‐benzo[ e ][1,3]thiazinones (BTZs) are potent in vitro antimycobacterial agents. New chemical transformations, viz . dearomatization and decarbonylation, of two BTZs and their influence on the compounds’ antimycobacterial properties are described. Reactions of 8‐nitro‐2‐(piperidin‐1‐yl)‐6‐(trifluoromethyl)‐4 H ‐benzo[ e ][1,3]thiazin‐4‐one and the clinical drug candidate BTZ043 with the Grignard reagent CH 3 MgBr afford the corresponding dearomatized stable 4,5‐dimethyl‐5 H ‐ and 4,7‐dimethyl‐7 H ‐benzo[ e ][1,3]thiazines. These methine compounds are structurally characterized by X‐ray crystallography for the first time. Reduction of the BTZ carbonyl group, leading to the corresponding markedly non‐planar 4 H ‐benzo[e][1,3]thiazine systems, is achieved using the reducing agent (CH 3 ) 2 S ⋅ BH 3 . Double methylation with dearomatization and decarbonylation renders the two BTZs studied inactive against Mycobacterium tuberculosis and Mycobacterium smegmatis , as proven by in vitro growth inhibition assays.