Novikova Daria, Al Mustafa Ammar, Grigoreva Tatyana, Vorona Svetlana, Selivanov Stanislav, Tribulovich Vyacheslav
Laboratory of Molecular Pharmacology, St. Petersburg State Institute of Technology, St. Petersburg 190013, Russia.
Laboratory of Biomolecular NMR, St. Petersburg State University, St. Petersburg 199034, Russia.
Molecules. 2023 Sep 12;28(18):6584. doi: 10.3390/molecules28186584.
Tetrahydropyrazolo[1,5-a]pyrimidine (THPP) is an attractive scaffold for designing biologically active compounds. The most obvious way to obtain such compounds is to reduce pyrazolopyrimidines with complex hydrides, because the pyrimidine ring is reduced in the preference over the pyrazole ring. The presence of substituents at positions five and seven of pyrazolo[1,5-a]pyrimidines complicates the set of reaction products but makes it more attractive for medicinal chemistry because four possible stereoisomers can be formed during reduction. However, the formation of only -isomers has been described in the literature. This article is the first report on the formation of -configured isomers along with -isomers in the reduction of model 5,7-dimethylpyrazolo[1,5-a]pyrimidine, which was confirmed by NMR. The bicyclic core in the -configuration was shown to be conformationally stable, which was used to estimate the long-range interproton distances using NOESY data. At the same time, long-range dipole-dipole interactions corresponding to a distance between protons of more than 6 Å were first registered and quantified. In turn, the bicyclic core in the -configuration represents a conformationally labile system. For these structures, an analysis of conformations observed in solutions was carried out. Our results indicate the significant potential of -configured tetrahydropyrazolo[1,5-a]pyrimidines for the development of active small molecules. While possessing structural lability due to the low energy of the conformational transition, they have the ability to adjust to the active site of the desired target.
四氢吡唑并[1,5 - a]嘧啶（THPP）是设计生物活性化合物的一个有吸引力的骨架。获得此类化合物最明显的方法是用复合氢化物还原吡唑并嘧啶，因为嘧啶环比吡唑环更易被还原。吡唑并[1,5 - a]嘧啶5位和7位上取代基的存在使反应产物的种类变得复杂，但对药物化学而言更具吸引力，因为还原过程中可形成四种可能的立体异构体。然而，文献中仅描述了 -异构体的形成。本文首次报道了在模型5,7 - 二甲基吡唑并[1,5 - a]嘧啶的还原反应中除了 -异构体还形成了 -构型异构体，这通过核磁共振得以证实。结果表明， -构型的双环核心具有构象稳定性，利用核欧沃豪斯效应（NOESY）数据可据此估算远程质子间距离。同时，首次记录并量化了对应质子间距离超过6 Å的远程偶极 - 偶极相互作用。反过来， -构型的双环核心代表一个构象不稳定的体系。针对这些结构，对溶液中观察到的构象进行了分析。我们的结果表明， -构型的四氢吡唑并[1,5 - a]嘧啶在开发活性小分子方面具有巨大潜力。尽管由于构象转变能量低而具有结构不稳定性，但它们有能力适应所需靶点的活性位点。
