Mech Paulina, Makowski Mariusz, Kawiak Anna, Chylewska Agnieszka
University of Gdańsk, Faculty of Chemistry, Department of Bioinorganic Chemistry ul. Wita Stwosza 63 80-308 Gdańsk Poland
Intercollegiate Faculty of Biotechnology of University of Gdańsk and Medical University of Gdańsk, Laboratory of Plant Protection and Biotechnology ul. Abrahama 58 80-307 Gdańsk Poland.
RSC Adv. 2020 Nov 9;10(67):40673-40688. doi: 10.1039/d0ra06239a.
The design of drug structures that are non-toxic, easily transported and permeable to cellular barriers is currently one of the most growing research trends. Indeed, the structural similarity of 2-hydrazinopyrazine (2HP) to pyrazinamide, which has been successfully used in anti-tuberculosis therapy, makes 2HP a promising research object. Thus, herein, a complete analysis of the structure of 2HP and its physicochemical and cytotoxic properties was performed. DNA (-DNA) and bovine serum albumin (BSA) binding studies were conducted, which demonstrated the higher affinity of 2HP to BSA. Furthermore, cytotoxicity tests were performed, which proved that 2HP was non-toxic to human skin keratinocyte cells. Accordingly, 2HP was initially classified as a compound with potential application. Physicochemical investigations were performed using a wide range of experiments, which were supported by DFT calculations using the B3LYP functional and 6-311+G** basis set. The good correlation, high quality and correctness of the obtained parameters were proven although the data was obtained using independent techniques. Additionally, 42 tautomeric (prototrophic) forms of 2HP were found by searching the conformational hyperspace. The most energy stable 2HP conformer structure and the partial charge distribution were established. The preferred 2HP ionic forms preferred were presented, and models of the equilibrium occurring in aqueous solution were proposed. The hydrophilic character of 2HP was established based on the partition coefficient values determined by both experiment and theory. The PCM and SMD solvent models of water and -octanol were used.
设计无毒、易于运输且能穿透细胞屏障的药物结构是当前发展最为迅速的研究趋势之一。事实上，2-肼基吡嗪（2HP）与已成功用于抗结核治疗的吡嗪酰胺结构相似，这使得2HP成为一个有前景的研究对象。因此，本文对2HP的结构及其物理化学和细胞毒性性质进行了全面分析。进行了DNA（-DNA）和牛血清白蛋白（BSA）结合研究，结果表明2HP对BSA具有更高的亲和力。此外，还进行了细胞毒性测试，结果证明2HP对人皮肤角质形成细胞无毒。因此，2HP最初被归类为具有潜在应用价值的化合物。使用了广泛的实验进行物理化学研究，并通过使用B3LYP泛函和6-311+G**基组的密度泛函理论（DFT）计算提供支持。尽管数据是使用独立技术获得的，但所获得参数的良好相关性、高质量和正确性得到了证实。此外，通过搜索构象超空间发现了42种2HP的互变异构（质子营养）形式。确定了能量最稳定的2HP构象结构和部分电荷分布。给出了2HP优选的离子形式，并提出了水溶液中发生的平衡模型。基于实验和理论测定的分配系数值确定了2HP的亲水性。使用了水和正辛醇的极化连续介质模型（PCM）和自洽反应场溶剂模型（SMD）。
