Kapková Petra, Stiefl Nikolaus, Sürig Ulf, Engels Bernd, Baumann Knut, Holzgrabe Ulrike
Institute of Pharmacy and Food Chemistry, University of Würzburg, Würzburg, Germany.
Arch Pharm (Weinheim). 2003 Nov;336(11):523-40. doi: 10.1002/ardp.200300795.
A novel series of acetylcholinesterase (AChE) inhibitors of the bispyridinium type was synthesized and the inhibitory activity against AChE and butyrylcholinesterase (BChE) measured. In essence, the substitution pattern influenced the inhibitory potency against AChE, where the most active bispyridiniumoxime (TMB-4) was bisbenzyl substituted followed by monobenzyl substituted, bismethyl substituted, and unsubstituted derivatives of TMB-4. Hence, the bisbenzyl ether of TMB-4 was further investigated. In order to obtain diverse lipophilic and electronic properties for these bisbenzyl bispyridinium derivatives (so-called DUO series), the lateral ring substitution was systematically varied. The lowest IC(50) value against AChE found thus far in the DUO series was 0.34 microM. Docking studies were carried out to elucidate the differences in biological activity. A general binding mode for nearly all compounds could be identified by these investigations. In this binding mode, the docked ligands span the narrow, deeply buried active-site gorge, interacting with Trp84 at the bottom of the gorge, Tyr334 or Phe331 halfway down the gorge, and Trp279 at the peripheral anionic site at the mouth of the gorge. For specific ligands, additional interactions were found which helped to explain their deviating activity. Based on the promising characteristics of the novel acetylcholinesterase inhibitors presented, a series of structurally related, optimized candidates will be developed.
合成了一系列新型的双吡啶型乙酰胆碱酯酶（AChE）抑制剂，并测定了它们对AChE和丁酰胆碱酯酶（BChE）的抑制活性。从本质上讲，取代模式影响了对AChE的抑制效力，其中活性最高的双吡啶肟（TMB-4）是双苄基取代的，其次是单苄基取代、双甲基取代以及未取代的TMB-4衍生物。因此，对TMB-4的双苄基醚进行了进一步研究。为了使这些双苄基双吡啶衍生物（所谓的DUO系列）具有不同的亲脂性和电子性质，对侧环取代进行了系统的变化。在DUO系列中迄今发现的对AChE的最低IC(50)值为0.34微摩尔。进行了对接研究以阐明生物活性的差异。通过这些研究可以确定几乎所有化合物的一般结合模式。在这种结合模式中，对接的配体跨越狭窄、深埋的活性位点峡谷，与峡谷底部的Trp84、峡谷中部的Tyr334或Phe331以及峡谷口外周阴离子位点的Trp279相互作用。对于特定的配体，还发现了其他相互作用，这有助于解释它们不同的活性。基于所呈现的新型乙酰胆碱酯酶抑制剂的良好特性，将开发一系列结构相关的优化候选物。
