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

• DOI: 10.1016/j.ejmech.2023.115539
• Publication Date: 2023-06-09T02:15:11Z
• Authors: Phelelisiwe S. Dube; Lesetja J. Legoabe; Audrey Jordaan; Lester Sigauke; Digby F. Warner; Richard M. Beteck
• Keywords: ADME; Lead compound; Quinolone

Mycobacterium tuberculosis (Mtb) has an impermeable cell wall which gives it inherent ability to resist many antibiotics. DprE1, essential enzyme in Mtb synthesis, 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 need populate the development pipeline. Using scaffold hopping strategy, we imprinted benzenoid ring of PBTZ169 onto quinolone nucleus. Twenty-two compounds were synthesised screened activity against Mtb, with six exhibiting sub micromolar MIC90 <0.244 μM. Compound 25 further demonstrated sub-micromolar when evaluated wild-type fluoroquinolone-resistant strains. This compound maintained its P116S mutant strain but showed significant reduction tested C387S mutant.