Discovery and Optimization of Benzotriazine Di-N-Oxides Targeting Replicating and Nonreplicating Mycobacterium tuberculosis
Discovery and Optimization of Benzotriazine Di-N-Oxides Targeting Replicating and Nonreplicating Mycobacterium tuberculosis
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DOI：
10.1021/jm300123s
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发表时间：
2012-07-12
影响因子：
7.3
通讯作者：
Madrid, Peter B.
中科院分区：
文献类型：
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作者：
Chopra, Sidharth;Koolpe, Gary A.;Madrid, Peter B.
对复制型和非复制型结核分枝杆菌都具有杀菌作用的化合物可以更快地消除感染，从而缩短结核病治疗方案的时间。对一组被生物还原为细胞毒性物质的抗菌药物和抗癌药物类别的筛选表明，1，2，4-苯并三嗪二N-氧化物（BTO）对复制型和非复制型结核病具有强效杀菌作用。通过半经验分子轨道计算指导的药物化学优化，从该系列中鉴定出一种新的先导化合物（20 q），其对H37 Rv的MIC为0.31 μ g/mL，对Vero细胞的细胞毒性（CC 50）为25 μ g/mL。20 q对一组单药耐药的Mtb菌株也具有相当的效力，并且对Mtb的选择性活性显著高于一组其他病原性细菌菌株。20 q在L5178 Y MOLY试验中也为阴性，表明遗传毒性的可能性较低。这些数据沿着与测量的物理化学性质和药代动力学曲线表明，BTO有潜力被开发成一类新的抗结核药物。
Compounds bactericidal against both replicating and nonreplicating Mtb may shorten the length of TB treatment regimens by eliminating infections more rapidly. Screening of a panel of antimicrobial and anticancer drug classes that are bioreduced into cytotoxic species revealed that 1,2,4-benzotriazine di-N-oxides (BTOs) are potently bactericidal against replicating and nonreplicating Mtb. Medicinal chemistry optimization, guided by semiempirical molecular orbital calculations, identified a new lead compound (20q) from this series with an MIC of 0.31 mu g/mL against H37Rv and a cytotoxicity (CC50) against Vero cells of 25 mu g/mL. 20q also had equivalent potency against a panel of single-drug resistant strains of Mtb and remarkably selective activity for Mtb over a panel of other pathogenic bacterial strains. 20q was also negative in a L5178Y MOLY assay, indicating low potential for genetic toxicity. These data along with measurements of the physiochemical properties and pharmacokinetic profile demonstrate that BTOs have the potential to be developed into a new class of antitubercular drugs.