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Design, synthesis and biological evaluation of (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives as inhibitors of Mycobacterium tuberculosis bd oxidase
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2022-08-06 , DOI: 10.1016/j.ejmech.2022.114639
Amit Kumar 1 , Neetu Kumari 2 , Sandeep Bhattacherjee 1 , Umamageswaran Venugopal 2 , Shahid Parwez 3 , Mohammad Imran Siddiqi 3 , Manju Y Krishnan 4 , Gautam Panda 5
Affiliation  

New chemical scaffolds with novel mechanism of action are urgently needed for the treatment of drug resistant tuberculosis. The oxidative phosphorylation pathway of Mycobacterium tuberculosis consists of multiple clinically validated drug targets. This pathway can function through any one of the two terminal oxidases-the proton pumping cytochrome bc1-aa3 supercomplex, or the less energy efficient but high affinity cytochrome bd oxidase. Inhibiting the bc1 complex alone has been found bacteriostatic and not bactericidal. On the other hand, inhibition of both these oxidases turns lethal to the pathogen. In the present study, we used a bc1 complex mutant of M. tuberculosis to screen (Quinazoline 4-yloxy)acetamide and (4-oxoquinazoline-3(4H)-yl)acetamide derivatives against the alternate oxidase, i.e., cytochrome bd oxidase. Two molecules, S-021-0601 and S-021-0607 were found to inhibit the mutant with MICs 8 and 16 μM respectively, compared to MICs of 128 and 256 μM against the wild type M. tuberculosis. In the wild type, one of the compounds showed synergism with Q203, an inhibitor of bc1 complex, in inhibiting growth under aerobic conditions. Both compounds showed synergism with Q203 in depleting bacterial ATP and inhibiting oxygen consumption. Both the compounds at 32 μM (one-fourth or one-eighth of their MICs for wild type) were bactericidal to wild type bacteria under hypoxic condition, causing ∼1.9 log10 reduction in viable counts which increased to ∼4-log10 when combined with Q203.



中文翻译:

(Quinazoline 4-yloxy)acetamide 和 (4-oxoquinazoline-3(4H)-yl)acetamide 衍生物作为结核分枝杆菌 bd 氧化酶抑制剂的设计、合成和生物学评价

治疗耐药结核病迫切需要具有新作用机制的新型化学支架。结核分枝杆菌的氧化磷酸化途径由多个临床验证的药物靶点组成。该途径可以通过两种末端氧化酶中的任何一种发挥作用——质子泵细胞色素bc 1 -aa 3超复合物,或能量效率较低但亲和力高的细胞色素bd氧化酶。已发现单独抑制bc 1复合物是抑菌的而不是杀菌的。另一方面,对这两种氧化酶的抑制对病原体都是致命的。在本研究中,我们使用了bc 1结核分枝杆菌的复杂突变体筛选 (Quinazoline 4-yloxy) 乙酰胺和 (4-oxoquinazoline-3(4 H )-yl) 乙酰胺衍生物对抗交替氧化酶,即细胞色素bd氧化酶。发现两种分子 S-021-0601 和 S-021-0607 抑制突变体的 MIC 分别为 8 和 16 μM,而对野生型结核分枝杆菌的 MIC 分别为 128 和 256 μM 。在野生型中,其中一种化合物与bc 1抑制剂 Q203 有协同作用复杂,在有氧条件下抑制生长。两种化合物在消耗细菌 ATP 和抑制氧气消耗方面都显示出与 Q203 的协同作用。两种浓度为 32 μM 的化合物(野生型 MIC 的四分之一或八分之一)在缺氧条件下对野生型细菌具有杀菌作用,导致活菌数减少约 1.9 log 10 ,组合时增加至约 4 - log 10与 Q203。

更新日期:2022-08-06
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