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First unequivocal identification of the critical acyl radicals from the anti-tuberculosis drug isoniazid and its hydrazide analogs by complementary applications of ESR spin-trapping and HPLC/MS methods.
Free Radical Biology and Medicine ( IF 7.1 ) Pub Date : 2020-04-30 , DOI: 10.1016/j.freeradbiomed.2020.04.021 Li Qin 1 , Chun-Hua Huang 1 , Li Mao 1 , Bo Shao 2 , Ben-Zhan Zhu 3
Free Radical Biology and Medicine ( IF 7.1 ) Pub Date : 2020-04-30 , DOI: 10.1016/j.freeradbiomed.2020.04.021 Li Qin 1 , Chun-Hua Huang 1 , Li Mao 1 , Bo Shao 2 , Ben-Zhan Zhu 3
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The carbon-centered isonicotinic acyl radical of isoniazid (INH), a widely-used frontline anti-tuberculosis drug, has been considered to play a critical role in inhibiting Mycobacterium tuberculosis, but not fully identified. Here we show that this radical intermediate can be unequivocally characterized by complementary applications of ESR spin-trapping and HPLC/MS methods by employing N-tert-butyl-α-phenylnitrone (PBN) as the suitable spin-trapping agent, which can form the most stable radical adduct. More importantly, for the first time, analogous carbon-centered acyl radicals and their respective NAD+ adducts have also been detected and identified from its two isomers (nicotinic acid hydrazide and 2-pyridinecarbohydrazide) and benzhydrazide which are structurally-related to INH, but not by 2-chloroisonicotinohydrazide. This study represents the first unequivocal identification of the carbon-centered acyl radicals of INH and other hydrazide analogs by both ESR spin-trapping and HPLC/MS methods, which may have broad biomedical and toxicological significance for future research for more efficient hydrazide anti-tuberculosis drugs.
中文翻译：
通过ESR旋转捕集和HPLC / MS方法的互补应用，从抗结核药异烟肼及其酰肼类似物中首次明确鉴定关键的酰基基团。
广泛使用的一线抗结核药物异烟肼（INH）的以碳为中心的异烟酸酰基被认为在抑制结核分枝杆菌中起关键作用，但尚未完全鉴定。在这里，我们表明，通过使用N-叔丁基-α-苯基硝酮（PBN）作为合适的自旋捕集剂，ESR自旋捕集和HPLC / MS方法的互补应用可以明确表征该自由基中间体，它可以形成最稳定的自由基加合物。更重要的是，还首次从结构上与INH相关但不相关的两个异构体（烟酸酰肼和2-吡啶碳酰肼）和苯甲酰肼中检测到并鉴定了类似的碳中心酰基基团及其各自的NAD +加合物。由2-氯异烟酰肼。
更新日期：2020-04-30
中文翻译：
通过ESR旋转捕集和HPLC / MS方法的互补应用，从抗结核药异烟肼及其酰肼类似物中首次明确鉴定关键的酰基基团。
广泛使用的一线抗结核药物异烟肼（INH）的以碳为中心的异烟酸酰基被认为在抑制结核分枝杆菌中起关键作用，但尚未完全鉴定。在这里，我们表明，通过使用N-叔丁基-α-苯基硝酮（PBN）作为合适的自旋捕集剂，ESR自旋捕集和HPLC / MS方法的互补应用可以明确表征该自由基中间体，它可以形成最稳定的自由基加合物。更重要的是，还首次从结构上与INH相关但不相关的两个异构体（烟酸酰肼和2-吡啶碳酰肼）和苯甲酰肼中检测到并鉴定了类似的碳中心酰基基团及其各自的NAD +加合物。由2-氯异烟酰肼。
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