Theodoridis Konstantinos, Charissopoulos Eleftherios, Tsioumela Dimitra, Pontiki Eleni
Laboratory of Pharmaceutical Chemistry, Faculty of Health Sciences, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
Molecules. 2025 Jul 27;30(15):3148. doi: 10.3390/molecules30153148.
In this study, the design and synthesis of a novel series of cinnamic acid and 1,2,4-triazole hybrids were reported, aiming to enhance antioxidant and lipoxygenase inhibitory activities through pharmacophore combination. Cinnamic acid derivatives and 1,2,4-triazoles exhibit a broad spectrum of biological activities; therefore, by synthesizing hybrid molecules, we would like to exploit the beneficial characteristics of each scaffold. The general synthetic procedure comprises three synthetic steps, starting from the reaction of appropriate substituted cinnamic acid with hydrazine monohydrate in acetonitrile with cyclohexane and resulting in the formation of hydrazides. Consequently, the hydrazides reacted with phenylisothiocyanate under microwave irradiation conditions. Then, cyclization proceeded to the 1,2,4-triazole after the addition of NaOH solution and microwave irradiation. All the synthesized derivatives have been studied for their ability (a) to interact with the free radical DPPH, (b) inhibit lipid peroxidation induced by AAPH, and (c) inhibit soybean lipoxygenase. The synthesized derivatives have shown significant antioxidant activity and have been proved to be very good lipoxygenase inhibitors. Compounds and (IC = 4.5 μM) are the most potent within the series followed by compound (IC = 5.0 μM). All the synthesized derivatives have been subjected to docking studies related to soybean lipoxygenase. Compound exhibited a docking score of -9.2 kcal/mol and formed hydrophobic interactions with Val126, Tyr525, Lys526, Arg533, and Trp772, as well as a π-cation interaction with Lys526.
在本研究中，报道了一系列新型肉桂酸与1,2,4 - 三唑杂化物的设计与合成，旨在通过药效团组合增强抗氧化和脂氧合酶抑制活性。肉桂酸衍生物和1,2,4 - 三唑具有广泛的生物活性；因此，通过合成杂化分子，我们希望利用每个支架的有益特性。一般合成步骤包括三个合成步骤，从适当取代的肉桂酸与水合肼在乙腈和环己烷中反应开始，生成酰肼。随后，酰肼在微波辐射条件下与苯基异硫氰酸酯反应。然后，加入氢氧化钠溶液并进行微波辐射后，环化生成1,2,4 - 三唑。对所有合成的衍生物进行了以下能力研究：（a）与自由基DPPH相互作用；（b）抑制AAPH诱导的脂质过氧化；（c）抑制大豆脂氧合酶。合成的衍生物显示出显著的抗氧化活性，并被证明是非常好的脂氧合酶抑制剂。化合物 和 （IC = 4.5 μM）是该系列中最有效的，其次是化合物 （IC = 5.0 μM）。所有合成的衍生物都进行了与大豆脂氧合酶相关的对接研究。化合物 表现出 - 9.2 kcal/mol的对接分数，并与Val126、Tyr525、Lys526、Arg533和Trp772形成疏水相互作用，以及与Lys526形成π - 阳离子相互作用。
