Quinolone analogues of benzothiazinone: Synthesis, antitubercular structure-activity relationship and ADME profiling

Mycobacterium tuberculosis (Mtb) has an impermeable cell wall which gives it an inherent ability to resist many antibiotics. DprE1, an essential enzyme in Mtb cell wall synthesis, has been validated as a target for several TB drug candidates. The most potent and developmentally advanced DprE1 inhibitor, PBTZ169, is still undergoing clinical development. With high attrition rate, there is need to populate the development pipeline. Using a scaffold hopping strategy, we imprinted the benzenoid ring of PBTZ169 onto a quinolone nucleus. Twenty-two compounds were synthesised and screened for activity against Mtb, with six compounds exhibiting sub micromolar activity of MIC90 <0.244 & mu;M. Compound 25 further demonstrated sub-micromolar activity when evaluated against wild-type and fluoroquinolone-resistant Mtb strains. This compound maintained its sub-micromolar activity against a DprE1 P116S mutant strain but showed a significant reduction in activity when tested against the DprE1 C387S mutant.

Automated summary

Mycobacterium tuberculosis (Mtb) has an impermeable cell wall, making it resistant to many antibiotics. DprE1 is a crucial enzyme in Mtb cell wall synthesis, and has been identified as a target for potential tuberculosis drugs. PBTZ169 is the most promising DprE1 inhibitor, but more drug candidates are needed. By modifying the structure of PBTZ169, we synthesized 22 compounds and found that six of them exhibited sub-micromolar activity against Mtb. Compound 25 showed sub-micromolar activity against wild-type and fluoroquinolone-resistant Mtb strains.