Optimization of 1,2,3,4-Tetrahydroacridin-9(10H)-ones as Antimalarials Utilizing Structure-Activity and Structure-Property Relationships
Optimization of 1,2,3,4-Tetrahydroacridin-9(10H)-ones as Antimalarials Utilizing Structure-Activity and Structure-Property Relationships
复制标题
DOI：
10.1021/jm200015a
复制
发表时间：
2011-07-14
影响因子：
7.3
通讯作者：
Manetsch, Roman
中科院分区：
文献类型：
--
作者：
Cross, R. Matthew;Maignan, Jordany R.;Manetsch, Roman
1,2,3,4-四氢吖啶-9(10H)-酮 (THAs) 的抗疟活性自 20 世纪 40 年代以来就已为人所知，并且随着 20 世纪 70 年代吖啶二酮氟沙吖啶 (1) 及其类似物（如 1990 年代 WR 243251 (2a)）的开发而受到更多关注。这些化合物在临床开发之前就因活性欠佳、溶解度差和快速诱导寄生虫抗性而失败。此外，缺乏对 THA 核心支架的详细构效关系 (SAR) 研究，也不存在 SPR 研究。为了改进最初的发现，合成了几个系列的 1,2,3,4-四氢吖啶-9(10H)-酮，并以系统的方式进行测试，检查每种化合物的抗疟活性、溶解度和渗透性。此外，选择一组选定的化合物进行微粒体稳定性测试，以确定 THA 支架的理化性质。几种有效的化合物 (EC50 < 100 nM) 被确定对临床相关分离株 W2 和 TM90-C2B 具有活性，同时具有良好的理化特性，并且几乎没有交叉耐药性。
Antimalarial activity of 1,2,3,4-tetrahydroacridin-9(10H)-ones (THAs) has been known since the 1940s and has garnered more attention with the development of the acridinedione floxacrine (1) in the 1970s and analogues thereof such as WR 243251 (2a) in the 1990s. These compounds failed just prior to clinical development because of suboptimal activity, poor solubility, and rapid induction of parasite resistance. Moreover, detailed structure-activity relationship (SAR) studies of the THA core scaffold were lacking and SPR studies were nonexistent. To improve upon initial findings, several series of 1,2,3,4-tetrahydroacridin-9(10H)-ones were synthesized and tested in a systematic fashion, examining each compound for antimalarial activity, solubility, and permeability. Furthermore, a select set of compounds was chosen for microsomal stability testing to identify physicochemical liabilities of the THA scaffold. Several potent compounds (EC50 < 100 nM) were identified to be active against the clinically relevant isolates W2 and TM90-C2B while possessing good physicochemical properties and little to no cross-resistance.