Zajíčková Markéta, Prchal Lukáš, Vokřál Ivan, Nguyen Linh Thuy, Kurz Thomas, Gasser Robin, Bednářová Klára, Mičundová Magdalena, Lungerich Beate, Michel Oliver, Skálová Lenka
Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Heyrovského 1203, 50005 Hradec Králové, Czech Republic.
University Hospital Hradec Kralove, Biomedical Research Centre, Sokolska 581, 50005 Hradec Kralove, Czech Republic.
Pharmaceutics. 2022 Mar 30;14(4):754. doi: 10.3390/pharmaceutics14040754.
As a widely distributed parasitic nematode of ruminants, Haemonchus contortus has become resistant to most anthelmintic classes, there has been a major demand for new compounds against H. contortus and related nematodes. Recent phenotypic screening has revealed two compounds, designated as BLK127 and HBK4, that are active against H. contortus larvae. The present study was designed to assess the activity of these compounds against H. contortus eggs and adults, hepatotoxicity in rats and sheep, as well as biotransformation in H. contortus adults and the ovine liver. Both compounds exhibited no inhibitory effect on the hatching of eggs. The benzyloxy amide BLK127 significantly decreased the viability of adults in sensitive and resistant strains of H. contortus and showed no hepatotoxic effect, even at the highest concentration tested (100 µM). In contrast, HBK4 had no impact on the viability of H. contortus adults and exhibited significant hepatotoxicity. Based on these findings, HBK4 was excluded from further studies, while BLK127 seems to be a potential candidate for a new anthelmintic. Consequently, biotransformation of BLK127 was tested in H. contortus adults and the ovine liver. In H. contortus, several metabolites formed via hydroxylation, hydrolysis and glycosidation were identified, but the extent of biotransformation was low, and the total quantity of the metabolites formed did not differ significantly between the sensitive and resistant strains. In contrast, ovine liver cells metabolized BLK127 more extensively with a glycine conjugate of 4-(pentyloxy)benzoic acid as the main BLK127 metabolite.
捻转血矛线虫作为一种广泛分布的反刍动物寄生线虫，已对大多数驱虫药产生抗性，因此对针对捻转血矛线虫及相关线虫的新型化合物有很大需求。最近的表型筛选发现了两种化合物，命名为BLK127和HBK4，它们对捻转血矛线虫幼虫具有活性。本研究旨在评估这些化合物对捻转血矛线虫虫卵和成虫的活性、对大鼠和绵羊的肝毒性以及在捻转血矛线虫成虫和绵羊肝脏中的生物转化。两种化合物对虫卵孵化均无抑制作用。苄氧基酰胺BLK127显著降低了捻转血矛线虫敏感株和抗性株成虫的活力，即使在最高测试浓度（100 μM）下也未表现出肝毒性。相比之下，HBK4对捻转血矛线虫成虫的活力没有影响，但表现出显著的肝毒性。基于这些发现，HBK4被排除在进一步研究之外，而BLK127似乎是一种新型驱虫药的潜在候选物。因此，对BLK127在捻转血矛线虫成虫和绵羊肝脏中的生物转化进行了测试。在捻转血矛线虫中，鉴定出了几种通过羟基化、水解和糖基化形成的代谢产物，但生物转化程度较低，敏感株和抗性株形成的代谢产物总量没有显著差异。相比之下，绵羊肝细胞对BLK127的代谢更广泛，4-(戊氧基)苯甲酸的甘氨酸共轭物是BLK127的主要代谢产物。
