Department of Applied Chemistry, Faculty of Textile Technology, University of Zagreb, Prilaz baruna Filipovića 28a, 10000 Zagreb, Croatia.
Org Biomol Chem. 2021 Mar 28;19(12):2784-2793. doi: 10.1039/d1ob00235j. Epub 2021 Mar 11.
Unlike the closely related and widely investigated amidino-substituted benzimidazoles and benzothiazoles with a range of demonstrated biological activities, the matching benzoxazole analogues still remain a largely understudied and not systematically evaluated class of compounds. To address this challenge, we utilized the Pinner reaction to convert isomeric cyano-substituted 2-aminophenols into their amidine derivatives, which were isolated as hydrochlorides and/or zwitterions, and whose structure was confirmed by single crystal X-ray diffraction. The key step during the Pinner synthesis of the crucial carboximidate intermediates was characterized through mechanistic DFT calculations, with the obtained kinetic and thermodynamic parameters indicating full agreement with the experimental observations. The obtained amidines were subjected to a condensation reaction with aryl carboxylic acids that allowed the synthesis of a new library of 5- and 6-amidino substituted 2-arylbenzoxazoles. Their antiproliferative features against four human tumour cell lines (SW620, HepG2, CFPAC-1, HeLa) revealed sub-micromolar activities on SW620 for several cyclic amidino 2-naphthyl benzoxazoles, thus demonstrating the usefulness of the proposed synthetic strategy and promoting amidino substituted 2-aminophenols as important building blocks towards biologically active systems.
与具有广泛研究和多种已证明生物活性的密切相关的氨甲酰取代苯并咪唑和苯并噻唑不同，匹配的苯并恶唑类似物仍然是一个在很大程度上未被充分研究且未被系统评估的化合物类别。为了解决这一挑战，我们利用 Pinner 反应将异构氰基取代的 2-氨基酚转化为其脒衍生物，这些衍生物以盐酸盐和/或两性离子的形式分离出来，并通过单晶 X 射线衍射确认了其结构。在关键的羧基脒中间体的 Pinner 合成过程中，关键步骤通过机理 DFT 计算进行了表征，获得的动力学和热力学参数与实验观察结果完全一致。得到的脒与芳基羧酸进行缩合反应，合成了一系列新的 5-和 6-氨甲酰取代的 2-芳基苯并恶唑。它们对四种人类肿瘤细胞系（SW620、HepG2、CFPAC-1、HeLa）的抗增殖特性表明，几种环状氨甲酰基 2-萘基苯并恶唑对 SW620 具有亚微摩尔活性，从而证明了所提出的合成策略的有效性，并推动了氨甲酰取代的 2-氨基酚作为生物活性系统的重要构建块。
