College of Pharmacy, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, Nebraska 986125, United States.
Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.
J Med Chem. 2020 Apr 9;63(7):3723-3736. doi: 10.1021/acs.jmedchem.0c00069. Epub 2020 Mar 19.
Semisynthetic artemisinins and other bioactive peroxides are best known for their powerful antimalarial activities, and they also show substantial activity against schistosomes-another hemoglobin-degrading pathogen. Building on this discovery, we now describe the initial structure-activity relationship (SAR) of antischistosomal ozonide carboxylic acids OZ418 () and OZ165 (). Irrespective of lipophilicity, these ozonide weak acids have relatively low aqueous solubilities and high protein binding values. Ozonides with -substituted carboxymethoxy and -benzylglycine substituents had high antischistosomal efficacies. It was possible to increase solubility, decrease protein binding, and maintain the high antischistosomal activity in mice infected with juvenile and adult by incorporating a weak base functional group in these compounds. In some cases, adding polar functional groups and heteroatoms to the spiroadamantane substructure increased the solubility and metabolic stability, but in all cases decreased the antischistosomal activity.
半合成青蒿素和其他生物活性过氧化物以其强大的抗疟活性而闻名，它们对血吸虫病（另一种破坏血红蛋白的病原体）也具有显著的活性。基于这一发现，我们现在描述了抗血吸虫病臭氧化物羧酸 OZ418（）和 OZ165（）的初始结构-活性关系（SAR）。这些臭氧弱酸无论亲脂性如何，在水中的溶解度相对较低，与蛋白质的结合值较高。具有 -取代的羧甲氧甲基和 -苄基甘氨酸取代基的臭氧化物具有很高的抗血吸虫病功效。通过在这些化合物中引入弱碱性官能团，可以提高溶解度、降低蛋白质结合，并保持对感染幼年和成年的小鼠的高抗血吸虫病活性。在某些情况下，向螺环金刚烷子结构中添加极性官能团和杂原子会增加溶解度和代谢稳定性，但在所有情况下都会降低抗血吸虫病活性。
