Solubility-driven optimization of benzothiopyranone salts leading to a preclinical candidate with improved pharmacokinetic properties and activity against Mycobacterium tuberculosis

Solubility-driven optimization of the salts of nitro benzothiopyranone 1, which targets DprE1, led to an antimycobacterial preclinical candidate 2. Five pharmaceutically acceptable salts, including the maleate (2), fumarate (3), citrate (4, 5), and l-malate (6) of compound 1, were prepared via the salt formation reaction and evaluated for their physicochemical and pharmacokinetic properties. Compared with 1, all the target salts exhibited greatly increased aqueous solubility and improved oral bioavailability in mice. Maleate salt 2, which displayed higher chemical stability and lower log P, showed substantially improved bioavailability in rats and a much better in vivo effect compared with free base 1 at the same dose. The X-ray crystal structure of 2 revealed that the exposed hydrophilic piperazine-maleate moiety in the crystal structure cell may be critical in increasing the solubility of 2. Thus, this maleate salt 2 overcame the poor druggability of benzothiopyranone derivatives and was identified as a promising preclinical candidate for treating tuberculosis.