Laboratoire des Substances d'Origine Naturelle et Analogs Structuraux, UFR des Sciences pharmaceutiques et ingénierie de la santé, Université d'Angers, 16 Bd Daviers, 49045 Angers Cedex, France.
Mini Rev Med Chem. 2013 Jul;13(9):1311-26. doi: 10.2174/13895575113139990007.
Naturally occurring hydroxamic acid derivatives are biosynthesized by microorganisms (siderophores) and plants (benzoxazinoids). Recent developments in drug discovery have highlighted the numerous biological and pharmacological properties that the hydroxamic acid function may possess, leading to therapeutic applications. These properties may be explained by its ability to chelate metals via the presence of two oxygen atoms. Their pharmacological activities can be divided into three groups. The first concerns the ability of these hydroxamic acid derivatives to scavenge metals (particularly iron), which leads to antioxidant, antimicrobial and metal detoxification activities. The latter is largely used to treat iron overload in patients. The second group of activities is related to their ability to inhibit metallo-enzymes, which gives them a wide range of pharmacological effects: antimicrobial, anti-inflammatory and antitumor. The third group is linked to the capacity of these compounds to generate nitric oxide, which confers hypotensive activity. However, hydroxamates exhibit relatively low stability in vivo, which can be overcome by the synthesis of appropriately designed analogs. For this purpose, many different strategies have been proposed. In this review, we compare and discuss the various synthetic pathways used to obtain the most complex of them, the N-substituted hydroxamic acids. We conclude that among numerous protocols reported so far, the direct N-substitution of hydroxamic acids, the acylation of the appropriate N-O derivative and the direct oxidation of the corresponding amide allow for the synthesis of a wide range of new biologically active compounds.
天然存在的羟肟酸衍生物由微生物（铁载体）和植物（苯并恶嗪类）生物合成。药物发现的最新进展强调了羟肟酸功能可能具有的许多生物学和药理学特性，从而导致了治疗应用。其通过存在两个氧原子螯合金属的能力可以解释这些特性。它们的药理活性可以分为三组。第一组涉及这些羟肟酸衍生物通过螯合金属（特别是铁）来清除金属的能力，这导致了抗氧化、抗菌和金属解毒活性。后者主要用于治疗患者的铁过载。第二组活性与它们抑制金属酶的能力有关，这使它们具有广泛的药理作用：抗菌、抗炎和抗肿瘤。第三组与这些化合物产生一氧化氮的能力有关，这赋予它们降压活性。然而，羟肟酸在体内的稳定性相对较低，这可以通过合成适当设计的类似物来克服。为此，已经提出了许多不同的策略。在这篇综述中，我们比较和讨论了获得最复杂的 N-取代羟肟酸的各种合成途径。我们得出结论，在迄今为止报道的众多方案中，羟肟酸的直接 N-取代、适当的 N-O 衍生物的酰化和相应酰胺的直接氧化允许合成广泛的新的具有生物活性的化合物。
