Hydride-induced Meisenheimer complex formation reflects activity of nitro aromatic anti-tuberculosis compounds
Rui Liu1, Lowell Markley1, Patricia A Miller1
1Department of Chemistry and Biochemistry, University of Notre Dame Notre Dame IN 46556 USA mmiller1@nd.edu.
Abstract:
The formation efficiency of hydride-induced Meisenheimer complexes of nitroaromatic compounds is consistent with their anti-TB activities exemplied by MDL860 and benzothiazol N-oxide (BTO) analogs. Herein we report that nitro cyano phenoxybenzenes (MDL860 and analogs) reacted slowly and incompletely which reflected their moderate anti-TB activity, in contrast to the instantaneous reaction of BTO derivatives to quantitatively generate Meisenheimer complexes which corresponded to their enhanced anti-TB activity. These results were corroborated by mycobacterial and radiolabelling studies that confirmed inhibition of the DprE1 enzyme by BTO derivatives but not MDL860 analogs.
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