Laboratory of Diagnostic Parasitology, Chair and Department of Biology and Genetics, Faculty of Pharmacy, Medical University of Lublin, 4A Chodzki Street, 20-093 Lublin, Poland.
Chair and Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Lublin, 4A Chodzki Street, 20-093 Lublin, Poland.
J Adv Res. 2024 Jun;60:57-73. doi: 10.1016/j.jare.2023.07.004. Epub 2023 Jul 17.
Intestinal parasitic infections are neglected diseases and, due to the increasing resistance of parasites to available drugs, they pose an increasing therapeutic challenge. Therefore, there is a great need for finding new compounds with antiparasitic activity.
In this work, new thiosemicarbazide and 1,2,4-triazole derivatives were synthesized and tested for their anthelmintic activity.
The synthesis was carried out by classical methods of organic chemistry. Anthelmintic activity tests were carried out in vitro (Rhabditis sp., Haemonchus contortus, Strongylidae sp.) in vivo (Heligmosomoides polygyrus/bakeri), and in silico analysis was performed.
Quinoline-6-carboxylic acid derivative compounds were designed and synthesized. The highest activity in the screening tests in the Rhabditis model was demonstrated by compound II-1 with a methoxyphenyl substituent LC = 0.3 mg/mL. In the next stage of the research, compound II-1 was analyzed in the H. contortus model. The results showed that compound II-1 was active and had ovicidal (percentage of dead eggs > 45 %) and larvicidal (percentage of dead larvae > 75 %) properties. Studies in the Strongylidae sp. model confirmed the ovicidal activity of compound II-1 (percentage of dead eggs ≥ 55 %). In vivo studies conducted in the H. polygyrus/bakeri nematode model showed that the number of nematodes decreased by an average of 30 % under the influence of compound II-1. In silico studies have shown two possible modes of action of compound II-1, i.e. inhibition of tubulin polymerization and SDH. The test compound did not show any systemic toxic effects. Its influence on drug metabolism related to the activity of cytochrome CYP450 enzymes was also investigated.
The results obtained in the in vitro, in vivo, and in silico studies indicate that the test compound can be described as a HIT, which in the future may be used in the treatment of parasitic diseases in humans and animals.
肠道寄生虫感染是被忽视的疾病，由于寄生虫对现有药物的耐药性不断增加，它们对治疗构成了越来越大的挑战。因此，迫切需要寻找具有抗寄生虫活性的新化合物。
本工作合成了新的硫代缩氨基脲和 1,2,4-三唑衍生物，并测试了它们的驱虫活性。
采用经典的有机化学方法进行合成。驱虫活性测试在体外（Rhabditis sp.、Haemonchus contortus、Strongylidae sp.）、体内（Heligmosomoides polygyrus/bakeri）和体外进行，并进行了计算机模拟分析。
设计并合成了喹啉-6-羧酸衍生物。在 Rhabditis 模型的筛选试验中，具有甲氧基苯基取代基的化合物 II-1 表现出最高的活性，LC=0.3mg/mL。在研究的下一阶段，对化合物 II-1 在 H. contortus 模型中进行了分析。结果表明，化合物 II-1 具有杀卵（死亡卵百分比>45%）和杀幼虫（死亡幼虫百分比>75%）的特性。在 Strongylidae sp.模型中的研究证实了化合物 II-1 的杀卵活性（死亡卵百分比≥55%）。在 H. polygyrus/bakeri 线虫模型中的体内研究表明，化合物 II-1 的作用使线虫数量平均减少了 30%。计算机模拟研究表明，化合物 II-1 可能有两种作用模式，即抑制微管蛋白聚合和 SDH。该测试化合物没有表现出任何全身毒性作用。还研究了其对与细胞色素 CYP450 酶活性相关的药物代谢的影响。
在体外、体内和计算机模拟研究中获得的结果表明，该测试化合物可被描述为一种 HIT，它可能在未来用于治疗人类和动物的寄生虫病。
