Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Kreuzstrasse 2, CH-4123 Allschwil, Switzerland.
University of Basel, CH-4003 Basel, Switzerland.
ACS Infect Dis. 2023 Mar 10;9(3):643-652. doi: 10.1021/acsinfecdis.2c00581. Epub 2023 Feb 16.
Praziquantel, the only drug in clinical use for the treatment and control of schistosomiasis, is inactive against developing infections. Ozonides are synthetic peroxide derivatives inspired by the naturally occurring artemisinin and show particularly promising activity against juvenile schistosomes. We conducted an in-depth characterization of the and antischistosomal activity and pharmacokinetics of lead ozonide carboxylic acid OZ418 and four of its active analogs. , the ozonides featured rapid and consistent activity against schistosomula and adult schistosomes at double-digit micromolar EC values. Potency did not vary considerably between The zwitterionic OZ740 and OZ772 were more active compared to their non-amphoteric carboxylic acids OZ418 and OZ748, despite their much lower systemic plasma exposure (AUC). The most active compound was ethyl ester OZ780, which was rapidly transformed to its parent zwitterion OZ740 and achieved ED values of 35 ± 2.4 and 29 ± 2.4 mg/kg against adult and juvenile , respectively. Ozonide carboxylic acids represent promising candidates for further optimization and development due to their good efficacy against both life stages together with their broad activity range against all relevant parasite species.
吡喹酮是唯一用于治疗和控制血吸虫病的临床药物，但对正在发育中的感染无效。臭氧化物是受天然青蒿素启发而合成的过氧化物衍生物，对幼年血吸虫具有特别有希望的活性。我们对先导臭氧化物羧酸 OZ418 及其四个活性类似物进行了深入的抗血吸虫活性和药代动力学特征分析。结果表明，臭氧化物对尾蚴和成虫血吸虫具有快速且一致的双位数微摩尔 EC 值活性。在 之间，臭氧化物的活性没有显著差异。与非两性离子羧酸 OZ418 和 OZ748 相比，两性离子 OZ740 和 OZ772 的活性更高，尽管它们在全身血浆暴露（AUC）方面要低得多。最有效的化合物 是乙基酯 OZ780，它可迅速转化为其母体两性离子 OZ740，对成虫和幼体的 ED 值分别为 35±2.4 和 29±2.4mg/kg。臭氧化物羧酸由于对所有相关寄生虫物种具有广泛的活性范围，并且对两个生命阶段均具有良好的疗效，因此是进一步优化和开发的有希望的候选药物。
