Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
ChemMedChem. 2013 Jul;8(7):1138-60. doi: 10.1002/cmdc.201300050. Epub 2013 Jun 14.
Through our focused effort to discover new and effective agents against toxoplasmosis, a structure-based drug design approach was used to develop a series of potent inhibitors of the enoyl-acyl carrier protein (ACP) reductase (ENR) enzyme in Toxoplasma gondii (TgENR). Modifications to positions 5 and 4' of the well-known ENR inhibitor triclosan afforded a series of 29 new analogues. Among the resulting compounds, many showed high potency and improved physicochemical properties in comparison with the lead. The most potent compounds 16 a and 16 c have IC50 values of 250 nM against Toxoplasma gondii tachyzoites without apparent toxicity to the host cells. Their IC50 values against recombinant TgENR were found to be 43 and 26 nM, respectively. Additionally, 11 other analogues in this series had IC50 values ranging from 17 to 130 nM in the enzyme-based assay. With respect to their excellent in vitro activity as well as improved drug-like properties, the lead compounds 16 a and 16 c are deemed to be excellent starting points for the development of new medicines to effectively treat Toxoplasma gondii infections.
通过我们对发现新的有效抗弓形虫药物的集中努力，采用基于结构的药物设计方法，开发了一系列具有抗弓形虫烯酰基载体蛋白（ACP）还原酶（ENR）活性的新型抑制剂。对知名的 ENR 抑制剂三氯生的 5 位和 4'位进行修饰，得到了一系列 29 个新的类似物。在得到的化合物中，许多化合物的活性和理化性质与先导化合物相比都有显著提高。最有效的化合物 16a 和 16c 对弓形虫速殖子的 IC50 值分别为 250 nM 和 26 nM，而对宿主细胞没有明显的毒性。它们对重组 TgENR 的 IC50 值分别为 43 和 26 nM。此外，该系列中的其他 11 个类似物在基于酶的测定中 IC50 值在 17 到 130 nM 之间。鉴于其优异的体外活性和改善的类药性，先导化合物 16a 和 16c 被认为是开发有效治疗弓形虫感染的新药的极好起点。
