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8-Nitrobenzothiazinones (BTZs) typified by the second-generation analogue PBTZ169 are a new class of antitubercular agents. The activity of BTZs and lipophilicity are tightly coupled since the molecular target DprE1 is located in the mycobacterial cell envelope. A series of analogues was designed to address the notorious insolubility of the BTZs while preserving the required lipophilicity. This was accomplished by decreasing the molecular planarity and symmetry through bioisosteric replacement of the piperazine moiety of PBTZ169 with spirocyclic and bicyclic diamines. Several promising compounds with improved aqueous solubilities were identified with potent antitubercular activity. Compound 5 was identified as the most promising candidate based on its excellent antitubercular activity (MIC of 32 nM), more than 1000-fold improvement in solubility, 2-fold lower clearance in mouse and human microsomes relative to PBTZ169, and promising pharmacokinetic parameters.

Spirocyclic and Bicyclic 8-Nitrobenzothiazinones for Tuberculosis with Improved Physicochemical and Pharmacokinetic Properties