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Osmium-arene complexes with high potency towards Mycobacterium tuberculosis.
Metallomics ( IF 3.4 ) Pub Date : 2021-04-08 , DOI: 10.1093/mtomcs/mfab007
James P C Coverdale,Collette S Guy,Hannah E Bridgewater,Russell J Needham,Elizabeth Fullam,Peter J Sadler

The treatment of tuberculosis (TB) poses a major challenge as frontline therapeutic agents become increasingly ineffective with the emergence and spread of drug-resistant strains of Mycobacterium tuberculosis (Mtb). To combat this global health problem, new antitubercular agents with novel modes of action are needed. We have screened a close family of 17 organometallic half-sandwich Os(II) complexes [(arene)Os(phenyl-azo/imino-pyridine)(Cl/I)]+Y- containing various arenes (p-cymene, biphenyl, or terphenyl), and NMe2, F, Cl, or Br phenyl or pyridyl substituents, for activity towards Mtb in comparison with normal human lung cells (MRC5). In general, complexes with a monodentate iodido ligand were more potent than chlorido complexes, and the five most potent iodido complexes (MIC 1.25-2.5 µM) have an electron-donating Me2N or OH substituent on the phenyl ring. As expected, the counter anion Y (PF6-, Cl-, I-) had little effect on the activity. The pattern of potency of the complexes towards Mtb is similar to that towards human cells, perhaps because in both cases intracellular thiols are likely to be involved in their activation and their redox mechanism of action. The most active complex against Mtb is the p-cymene Os(II) NMe2-phenyl-azopyridine iodido complex (2), a relatively inert complex that also exhibits potent activity towards cancer cells. The uptake of Os from complex 2 by Mtb is rapid and peaks after 6 h, with temperature-dependence studies suggesting a major role for active transport. Significance to Metallomics Antimicrobial resistance is a global health problem. New advances are urgently needed in the discovery of new antibiotics with novel mechanisms of action. Half-sandwich organometallic complexes offer a versatile platform for drug design. We show that with an appropriate choice of the arene, an N,N-chelated ligand, and monodentate ligand, half-sandwich organo-osmium(II) complexes can exhibit potent activity towards Mycobacterium tuberculosis (Mtb), the leading cause of death from a single infectious agent. The patterns of activity of the 17 azo- and imino-pyridine complexes studied here towards Mtb and normal lung cells suggest a common redox mechanism of action involving intracellular thiols.

中文翻译:

对结核分枝杆菌具有高效力的锇-芳烃复合物。

随着结核分枝杆菌 (Mtb) 耐药菌株的出现和传播,一线治疗药物变得越来越无效,结核病 (TB) 的治疗成为一项重大挑战。为了解决这一全球健康问题,需要具有新作用方式的新型抗结核药物。我们筛选了 17 种有机金属半夹心 Os(II) 配合物 [(芳烃)Os(苯基-偶氮/亚氨基-吡啶)(Cl/I)]+Y- 的紧密家族,其中包含各种芳烃(对甲基异丙基苯、联苯、或三联苯)和 NMe2、F、Cl 或 Br 苯基或吡啶基取代基,与正常人肺细胞 (MRC5) 相比对 Mtb 的活性。一般来说,具有单齿碘配体的配合物比氯化配合物和五种最有效的碘配合物 (MIC 1.25-2. 5 µM) 在苯环上有一个供电子 Me2N 或 OH 取代基。正如预期的那样,抗衡阴离子 Y(PF6-、Cl-、I-)对活性几乎没有影响。复合物对 Mtb 的效力模式与对人类细胞的效力模式相似,这可能是因为在这两种情况下,细胞内硫醇都可能参与它们的活化及其氧化还原作用机制。对 Mtb 最活跃的复合物是对甲基异丙基苯 Os(II) NMe2-苯基-偶氮吡啶碘化物复合物 (2),这是一种相对惰性的复合物,对癌细胞也表现出有效的活性。Mtb 从复合物 2 中吸收 Os 是快速的,并在 6 小时后达到峰值,温度依赖性研究表明主动转运的主要作用。对金属组学的意义 抗菌素耐药性是一个全球性的健康问题。在发现具有新作用机制的新抗生素方面迫切需要新的进展。半夹心有机金属配合物为药物设计提供了一个多功能平台。We show that with an appropriate choice of the arene, an N,N-chelated ligand, and monodentate ligand, half-sandwich organo-osmium(II) complexes can exhibit potent activity towards Mycobacterium tuberculosis (Mtb), the leading cause of death from单一的传染媒介。此处研究的 17 种偶氮和亚氨基吡啶复合物对 Mtb 和正常肺细胞的活性模式表明了涉及细胞内硫醇的常见氧化还原作用机制。和单齿配体,半夹心有机锇(II)复合物可以对结核分枝杆菌(Mtb)表现出有效的活性,结核分枝杆菌是单一感染因子导致死亡的主要原因。此处研究的 17 种偶氮和亚氨基吡啶复合物对 Mtb 和正常肺细胞的活性模式表明了涉及细胞内硫醇的常见氧化还原作用机制。和单齿配体,半夹心有机锇(II)复合物可以对结核分枝杆菌(Mtb)表现出有效的活性,结核分枝杆菌是单一感染因子导致死亡的主要原因。此处研究的 17 种偶氮和亚氨基吡啶复合物对 Mtb 和正常肺细胞的活性模式表明了涉及细胞内硫醇的常见氧化还原作用机制。
更新日期:2021-04-08
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