Norwegian University of Science and Technology, Høgskoleringen 5, NO-7491 Trondheim, Norway.
Bioorg Chem. 2012 Oct;44:35-41. doi: 10.1016/j.bioorg.2012.06.003. Epub 2012 Jul 6.
A series 6-aryl-pyrrolo[2,3-d]pyrimidine-4-amines (43 compounds), some of which are epidermal growth factor tyrosine kinase inhibitors, were tested for their protozoal toxicity using an environmental Tetrahymena strain as model organism. The protozoacidal activity of the analogues was found to be highly dependent on a 4-hydroxyl group at the 6-aryl ring, and a chiral 1-phenylethanamine substituent in position 4. Further, the potency was affected by the aromatic substitution pattern of the phenylethanamine: the unsubstituted, the meta-fluoro and the para-bromo substituted derivatives had the lowest minimum protozoacidal concentrations (8-16 μg/mL). Surprisingly, both enantiomers were found to have high potency suggesting that this compound class could have several modes of action. No correlation was found between the compounds protozoacidal activity and the in vitro epidermal growth factor receptor tyrosine kinase inhibitory potency. This suggests that the observed antimicrobial effects are related to other targets. Testing towards a panel of kinases indicated several alternative modes of action.
一系列 6-芳基-吡咯并[2,3-d]嘧啶-4-胺（43 种化合物），其中一些是表皮生长因子酪氨酸激酶抑制剂，被测试了其原生动物毒性，使用环境四膜虫菌株作为模型生物。类似物的原生动物杀伤活性高度依赖于 6-芳基环上的 4-羟基和 4 位的手性 1-苯乙胺取代基。此外，效力还受到苯乙胺的芳香取代模式的影响：未取代、间氟和对溴取代的衍生物具有最低的最小原生动物杀伤浓度（8-16μg/mL）。令人惊讶的是，两种对映异构体都具有高活性，这表明此类化合物可能具有多种作用模式。未发现化合物的原生动物杀伤活性与体外表皮生长因子受体酪氨酸激酶抑制活性之间存在相关性。这表明观察到的抗菌作用与其他靶点有关。针对一组激酶的测试表明了几种替代作用模式。
