Escuela de Ingeniería Química, Facultad de Ingeniería Química y Textil, Universidad Nacional de Ingeniería, Lima, Peru; Laboratorio de Biopolímeros y Metalofármacos, LIBIPMET, Facultad de Ciencias, Universidad Nacional de Ingeniería, Lima, Peru.
Área Química Inorgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay.
J Inorg Biochem. 2022 Feb;227:111683. doi: 10.1016/j.jinorgbio.2021.111683. Epub 2021 Dec 3.
Despite being a preventable and curable disease, Tuberculosis (TB) is the world's top infectious killer. Development of new drugs is urgently needed. In this work, the synthesis and characterization of new silver(I) complexes, that include N'-[(E)-(pyridine-2-ylmethylene)pyrazine-2-carbohydrazide, HPCPH, as main ligand and substituted aryl-phosphines as auxiliary ligands, is reported. HPCPH was synthesized from pyrazinoic acid, the active metabolite of the first-line antimycobacterial drug pyrazinamide. Complexes [Ag(HPCPH)(PPh)]OTf (1), [Ag(HPCPH)((P(p-tolyl))]OTf (2) and [Ag(HPCPH)(P(p-anisyl))]OTf (3) were characterized in solid state and in solution by elemental analysis and FTIR and NMR spectroscopies (OTftriflate). Crystal structures of (1,2) were determined by XRD. The Ag atom is coordinated to azomethine and pyridine nitrogen atoms of HPCPH ligand and to the phosphorous atom of each aryl-phosphine co-ligand. Although HPCPH did not show activity, the Ag(I) compounds demonstrated activity against Mycobacterium tuberculosis (MTB), HRv strain, and multi-drug resistant clinical isolates (MDR-TB). Globally, results showed that the compounds are not only effective against the sensitive strain, but are more potent against MDR-TB than antimycobacterial drugs used in therapy. The compounds showed low to moderate selectivity index values (SI) towards the bacteria, using MRC-5 cells (ATCC CCL-171) as mammalian cell model. Interaction with DNA was explored to get insight into the potential mechanism of action against the pathogen. No significant interaction was detected, allowing to discard this biomolecule as a potential molecular target. Compound 1 was identified as a hit compound (MIC 2.23 μM; SI 4.4) to develop further chemical modifications in the search for new drugs.
尽管结核病 (TB) 是一种可预防和可治愈的疾病，但它仍是全球头号传染病杀手。因此，急需开发新的药物。在这项工作中，报告了新的银 (I) 配合物的合成和表征，这些配合物包括 N'-[(E)-(吡啶-2-基亚甲基)吡嗪-2-甲酰肼，HPCPH，作为主要配体和取代的芳基膦作为辅助配体。HPCPH 是由吡嗪酸合成的，吡嗪酸是一线抗分枝杆菌药物吡嗪酰胺的活性代谢物。配合物 [Ag(HPCPH)(PPh)]OTf (1)、[Ag(HPCPH)((P(p- 甲苯基))]OTf (2) 和 [Ag(HPCPH)(P(p- 甲氧基苯基))]OTf (3) 在固态和溶液中通过元素分析和 FTIR 和 NMR 光谱 (OTftriflate) 进行了表征。(1,2) 的晶体结构通过 XRD 确定。Ag 原子与 HPCPH 配体的亚胺和吡啶氮原子以及每个芳基膦辅助配体的磷原子配位。尽管 HPCPH 本身没有活性，但 Ag(I) 化合物对结核分枝杆菌 (MTB)、HRv 株和多药耐药临床分离株 (MDR-TB) 表现出活性。全球范围内，结果表明，这些化合物不仅对敏感株有效，而且对 MDR-TB 的活性比治疗中使用的抗分枝杆菌药物更强。这些化合物对细菌的选择性指数值 (SI) 较低至中等，使用 MRC-5 细胞 (ATCC CCL-171) 作为哺乳动物细胞模型。还研究了与 DNA 的相互作用，以深入了解针对病原体的潜在作用机制。未检测到明显的相互作用，因此可以排除这种生物分子作为潜在的分子靶标。化合物 1 被鉴定为命中化合物 (MIC 2.23 μM；SI 4.4)，以进一步进行化学修饰，以寻找新的药物。
