Identification of Better Pharmacokinetic Benzothiazinone Derivatives as New Antitubercular Agents

Abstract

A series of new 8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one(BTZ) derivatives containing a C-2 nitrogen spiro-heterocycle moiety based on the structures of BTZ candidates BTZ043 and PBTZ169 were designed and synthesized as new antitubercular agents. Many of them were found to have excellent <i>in vitro</i> activity (MIC < 0.15 μM) against the drug susceptive <i>Mycobacterium tuberculosis</i> H37Rv strain and two clinically isolated multidrug-resistant strains. Compounds <b>11l</b> and <b>11m</b> display acceptable safety, greater aqueous solubility, and better pharmacokinetic profiles than PBTZ169, suggesting their promising potential to be lead compounds for future antitubercular drug discovery.