Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, SY23 3DA Wales, UK; Institute of Parasitology, Biology Centre, Czech Academy of Sciences, České Budějovice 370 05, Czech Republic.
Naturiol Bangor Ltd., MSParc, Gaerwen, Anglesey LL60 6AG, UK.
Vet Parasitol. 2022 Sep;309:109766. doi: 10.1016/j.vetpar.2022.109766. Epub 2022 Jul 20.
Control of liver fluke infections remains a significant challenge in the livestock sector due to widespread distribution of drug resistant parasite populations. In particular, increasing prevalence and economic losses due to infection with Fasciola hepatica is a direct result of drug resistance to the gold standard flukicide, triclabendazole. Sustainable control of this significant zoonotic pathogen, therefore, urgently requires the identification of new anthelmintics. Plants represent a source of molecules with potential flukicidal effects and, amongst their secondary metabolites, the diterpenoid abietic acids can be isolated in large quantities. In this study, nineteen (19) chemically modified abietic acid analogues (MC_X) were first evaluated for their anthelmintic activities against F. hepatica newly excysted juveniles (NEJs, from the laboratory-derived Italian strain); from this, 6 analogues were secondly evaluated for their anthelmintic activities against adult wild strain flukes. One analogue, MC010, was progressed further against 8-week immature- and 12-week mature Italian strain flukes. Here, MC010 demonstrated moderate activity against both of these intra-mammalian fluke stages (with an adult fluke EC = 12.97 µM at 72 h post culture). Overt mammalian cell toxicity of MC010 was inferred from the Madin-Darby bovine kidney (MDBK) cell line (CC = 17.52 µM at 24 h post culture) and demonstrated that medicinal chemistry improvements are necessary before abietic acid analogues could be considered as potential anthelmintics against liver fluke pathogens.
由于耐药寄生虫种群的广泛分布，控制肝吸虫感染仍然是畜牧业面临的重大挑战。特别是，由于对金标准驱虫药三氯苯达唑的耐药性，导致 Fasciola hepatica 的感染率不断上升和经济损失，这是直接导致耐药性的原因。因此，迫切需要识别新的驱虫药来控制这种重要的人畜共患病原体。植物是具有潜在驱虫作用的分子的来源，在其次生代谢产物中，可以大量分离出二萜类松香酸。在这项研究中，首先评估了 19 种（19 种）化学修饰的枞酸类似物（MC_X）对新孵化的肝片吸虫幼虫（NEJ，来自实验室衍生的意大利株）的驱虫活性；其中，有 6 种类似物对成年野生株肝片吸虫的驱虫活性进行了评估。一种类似物 MC010 进一步针对 8 周龄未成熟和 12 周龄成熟的意大利株肝片吸虫进行了研究。结果表明，MC010 对这两个哺乳动物阶段的肝片吸虫都具有中等活性（在 72 小时后培养，成虫 EC = 12.97µM）。从马-达比牛肾（MDBK）细胞系（在培养后 24 小时，CC = 17.52µM）推断出 MC010 对哺乳动物细胞的毒性，表明在将松香酸类似物作为潜在的抗肝片吸虫病原体驱虫剂之前，有必要进行药物化学改进。
