Griffith Institute for Drug Discovery, School of Environment and Science, Griffith University, Brisbane, QLD 4111, Australia.
Department of Veterinary Biosciences, Melbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, VIC 3010, Australia.
J Nat Prod. 2023 Mar 24;86(3):557-565. doi: 10.1021/acs.jnatprod.2c01041. Epub 2023 Feb 17.
The known -derived diterpenoid 3,7,8-trihydroxyserrulat-14-en-19-oic acid () was targeted for large-scale purification, as this bioactive plant compound has proven to be an attractive scaffold for semisynthetic studies and subsequent library generation. Compound was converted to a selectively protected trimethyl derivative, 3-hydroxy-7,8-dimethoxyserrulat-14-en-19-oic acid methyl ester (), using simple and rapid methylation conditions. The resulting scaffold was reacted with a diverse series of commercially available isocyanates to generate an 11-membered carbamate-based library. The chemical structures of the 11 new semisynthetic analogues were fully characterized by spectroscopic and spectrometric analysis. All natural products and semisynthetic compounds were evaluated for their anthelmintic, antimalarial, and anti-HIV activities. Compound was shown to elicit the greatest antiplasmodial activity of all compounds tested, with IC values of 4.6 and 11.6 μM against 3D7 and Dd2, respectively. Compound showed the greatest inhibition of development to fourth-stage larvae (L4) and induction of a skinny () phenotype (67.5% of nematodes) at 50 μM. Compound , which inhibited 59.0% of HIV production at 100 μg/mL, was the carbamate analogue that displayed the best antiviral activity.
已知衍生的二萜 3,7,8-三羟基蛇麻烯-14-烯-19-酸 () 是大规模纯化的目标，因为这种具有生物活性的植物化合物已被证明是半合成研究和随后的文库生成的有吸引力的支架。使用简单快速的甲基化条件，将化合物 转化为选择性保护的三甲基衍生物 3-羟基-7,8-二甲氧基蛇麻烯-14-烯-19-酸甲酯 ()。所得支架 与一系列商业可得的异氰酸酯反应，生成基于 11 元氨基甲酸酯的文库。通过光谱和光谱分析充分表征了 11 种新的半合成类似物的化学结构。评估了所有天然产物和半合成化合物的驱虫、抗疟和抗 HIV 活性。结果表明，化合物 对所有测试化合物表现出最强的抗疟活性，对 3D7 和 Dd2 的 IC 值分别为 4.6 和 11.6 μM。化合物 在 50 μM 时对第四阶段幼虫 (L4) 的发育抑制作用最大，诱导瘦 ( ) 表型的发生率最高（67.5%的线虫）。在 100 μg/mL 时抑制 HIV 产生 59.0%的氨基甲酸酯类似物 表现出最佳的抗病毒活性。
