海洋天然产物(MNPs)继续主要在细胞毒性试验中进行测试,哺乳动物和微生物,尽管大多数在与药物发现相关的浓度下不活跃。这些MNPs成为错失的机会,代表了对宝贵生物资源的浪费。与已发表的生物活性数据一致的化学信息学的使用可以提供见解,以指导选择生物测定来评估新的MNPs。截至2023年底,在MarinLit(n=39,730)中发现的MNPs的化学信息学分析突出了吲哚-3-基-乙醛酸酰胺(IGAs,n=24)作为一组MNPs,没有报道的生物活性。然而,最近对合成IGA的评论强调了这些支架是特权结构,有几种化合物正在临床评估中。在这里,我们报告了使用简单的一锅法合成32个MNP启发的溴化IGA(25-56)库,多步法提供了对这些不同化学支架的访问。通过对海洋吲哚生物碱(MIA)和合成IGA的生物活性进行荟萃分析,研究了溴化IGA25-56对帕金森病淀粉样蛋白α突触核蛋白(α-syn)的潜在生物活性,对恶性疟原虫的氯喹抗性(3D7)和敏感(Dd2)寄生虫菌株的抗疟原虫活性,和抑制哺乳动物(胰凝乳蛋白酶和弹性蛋白酶)和病毒(SARS-CoV-23CLpro)蛋白酶。所有测试的合成IGA都表现出对淀粉样蛋白α-syn的结合亲和力,虽然一些显示出对恶性疟原虫的抑制活性,和蛋白酶,SARS-CoV-23CLpro,还有胰凝乳蛋白酶.针对癌性和非癌性人类细胞系检查了IGA的细胞安全性,所有测试的化合物都没有活性,从而验证化学信息学和荟萃分析结果。本文提出的发现扩展了我们对海洋IGA生物活性化学空间的了解,并主张扩大常规用于研究NP生物活性的生物测定的范围。特别是那些更适合无毒的化合物。通过将化学信息学工具和功能测定整合到NP生物测试工作流程中,我们的目标是增强NP及其支架的潜力,用于未来的药物发现和开发。
Marine natural products (MNPs) continue to be tested primarily in cellular toxicity assays, both mammalian and microbial, despite most being inactive at concentrations relevant to drug discovery. These MNPs become missed opportunities and represent a wasteful use of precious bioresources. The use of
cheminformatics aligned with published bioactivity data can provide insights to direct the choice of bioassays for the evaluation of new MNPs.
Cheminformatics analysis of MNPs found in MarinLit (n = 39,730) up to the end of 2023 highlighted indol-3-yl-glyoxylamides (IGAs, n = 24) as a group of MNPs with no reported bioactivities. However, a recent review of synthetic IGAs highlighted these scaffolds as privileged structures with several compounds under clinical evaluation. Herein, we report the synthesis of a library of 32 MNP-inspired brominated IGAs (25-56) using a simple one-pot, multistep method affording access to these diverse chemical scaffolds. Directed by a meta-analysis of the biological activities reported for marine indole alkaloids (MIAs) and synthetic IGAs, the brominated IGAs 25-56 were examined for their potential bioactivities against the Parkinson\'s Disease amyloid protein alpha synuclein (α-syn), antiplasmodial activities against chloroquine-resistant (3D7) and sensitive (Dd2) parasite strains of Plasmodium falciparum, and inhibition of mammalian (chymotrypsin and elastase) and viral (SARS-CoV-2 3CLpro) proteases. All of the synthetic IGAs tested exhibited binding affinity to the amyloid protein α-syn, while some showed inhibitory activities against P. falciparum, and the proteases, SARS-CoV-2 3CLpro, and chymotrypsin. The cellular safety of the IGAs was examined against cancerous and non-cancerous human cell lines, with all of the compounds tested inactive, thereby validating
cheminformatics and meta-analyses results. The findings presented herein expand our knowledge of marine IGA bioactive chemical space and advocate expanding the scope of biological assays routinely used to investigate NP bioactivities, specifically those more suitable for non-toxic compounds. By integrating
cheminformatics tools and functional assays into NP biological testing workflows, we can aim to enhance the potential of NPs and their scaffolds for future drug discovery and development.