Education Mega Center, Guangdong University of Technology, School of Chemical Engineering and Light Industry, No. 100 Waihuan Xi Road, Guangzhou, P. R. China.
Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, BP 44099, 31077 Toulouse Cedex 4, France.
Org Biomol Chem. 2023 Sep 20;21(36):7382-7394. doi: 10.1039/d3ob01122d.
Since the Covid-19 epidemic, it has been clear that the availability of small and affordable drugs that are able to efficiently control viral infections in humans is still a challenge in medicinal chemistry. The synthesis and biological activities of a series of hybrid molecules that combine an emodin moiety and other structural moieties expected to act as possible synergistic pharmacophores in a single molecule were studied. Emodin has been reported to block the entry of the SARS-CoV-2 virus into human cells and might also inhibit cytokine production, resulting in the reduction of pulmonary injury induced by SARS-CoV-2. The pharmacophore associated with emodin was either a polyamine residue (emodin-PA series), a choice driven by the fact that a natural alkyl PA like spermine and spermidine play regulatory roles in immune cell functions, or a diphenylmethylpiperazine derivative of the norchlorcyclizine series (emoxyzine series). In fact, diphenylmethylpiperazine antagonists of the H1 histamine receptor display activity against several viruses by multiple interrelated mechanisms. In the emoxyzine series, the most potent drug against SARS-CoV-2 was ()-emoxyzine-2, with an EC value = 1.9 μM, which is in the same range as that of the reference drug remdesivir. However, the selectivity index was rather low, indicating that the dissociation of antiviral potency and cytotoxicity remains a challenge. In addition, since emodin was also reported to be a relatively high-affinity inhibitor of the virulence regulator FIKK kinase from the malaria parasite , the antimalarial activity of the synthesized hybrid compounds has been evaluated. However, these molecules cannot efficiently compete with the currently used antimalarial drugs.
自新冠疫情以来，显然能够高效控制人类病毒感染的小型且价格实惠的药物的供应，仍然是药物化学领域的一项挑战。本研究合成并测试了一系列杂合分子的生物活性，这些杂合分子结合了大黄素部分和其他结构部分，预计这些结构部分在单个分子中可起到协同药效团的作用。据报道，大黄素可阻止 SARS-CoV-2 病毒进入人体细胞，还可能抑制细胞因子的产生，从而减少 SARS-CoV-2 引起的肺损伤。与大黄素相关的药效团是多胺残基（大黄素-PA 系列），选择该药效团的原因是天然烷基多胺，如精胺和亚精胺，在免疫细胞功能的调节中发挥作用，或者是 norchlorcyclizine 系列的二苯甲基哌嗪衍生物（依莫唑嗪系列）。事实上，H1 组胺受体的二苯甲基哌嗪拮抗剂通过多种相互关联的机制对多种病毒具有活性。在依莫唑嗪系列中，对 SARS-CoV-2 最有效的药物是（）-依莫唑嗪-2，EC 值=1.9 μM，与对照药物瑞德西韦相当。然而，选择性指数相当低，表明抗病毒效力与细胞毒性的脱钩仍然是一项挑战。此外，由于大黄素也被报道为疟原虫毒力调节因子 FIKK 激酶的相对高亲和力抑制剂，因此评估了合成杂合化合物的抗疟活性。然而，这些分子不能有效地与目前使用的抗疟药物竞争。
