化学
广告
喹诺酮类
结核分枝杆菌
突变体
铅化合物
立体化学
组合化学
酶
微生物学
生物化学
体外
抗生素
肺结核
基因
生物
病理
医学
作者
Phelelisiwe S. Dube,Lesetja J. Legoabe,Audrey Jordaan,Lester T. Sigauke,Digby F. Warner,Richard M. Beteck
标识
DOI:10.1016/j.ejmech.2023.115539
摘要
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 μM. 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.
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