Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
Bioorg Med Chem Lett. 2013 Apr 1;23(7):2035-43. doi: 10.1016/j.bmcl.2013.02.019. Epub 2013 Feb 13.
Triclosan is a potent inhibitor of Toxoplasma gondii enoyl reductase (TgENR), which is an essential enzyme for parasite survival. In view of triclosan's poor druggability, which limits its therapeutic use, a new set of B-ring modified analogs were designed to optimize its physico-chemical properties. These derivatives were synthesized and evaluated by in vitro assay and TgENR enzyme assay. Some analogs display improved solubility, permeability and a comparable MIC50 value to that of triclosan. Modeling of these inhibitors revealed the same overall binding mode with the enzyme as triclosan, but the B-ring modifications have additional interactions with the strongly conserved Asn130.
三氯生是刚地弓形虫烯醇还原酶（TgENR）的有效抑制剂，该酶是寄生虫存活所必需的一种关键酶。鉴于三氯生的成药性较差，限制了其治疗用途，设计了一组新的 B 环修饰类似物以优化其理化性质。通过体外测定法和 TgENR 酶测定法对这些衍生物进行了合成和评估。一些类似物显示出改善的溶解度、通透性和与三氯生相当的 MIC50 值。这些抑制剂的建模显示与酶的整体结合模式与三氯生相同，但 B 环修饰与高度保守的 Asn130 有额外的相互作用。
