Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
Malar J. 2010 Feb 11;9:51. doi: 10.1186/1475-2875-9-51.
The clinical utility for mefloquine has been eroded due to its association with adverse neurological effects. Better-tolerated alternatives are required. The objective of the present study was the identification of lead compounds that are as effective as mefloquine, but exhibit physiochemical properties likely to render them less susceptible to passage across the blood-brain barrier.
A library of drug-like non-piperidine analogs of mefloquine was synthesized. These compounds are diverse in structure and physiochemical properties. They were screened in appropriate in vitro assays and evaluated in terms of their potential as lead compounds. The correlation of specific structural attributes and physiochemical properties with activity was assessed.
The most potent analogs were low molecular weight unconjugated secondary amines with no heteroatoms in their side-chains. However, these compounds were more metabolically labile and permeable than mefloquine. In terms of physiochemical properties, lower polar surface area, lower molecular weight, more freely rotatable bonds and fewer H-bond acceptors were associated with greater potency. There was no such relationship between activity and LogP, LogD or the number of hydrogen bond donors (HBDs). The addition of an H-bond donor to the side-chain yielded a series of active diamines, which were as metabolically stable as mefloquine but showed reduced permeability.
A drug-like library of non-piperidine analogs of mefloquine was synthesized. From amongst this library an active lead series of less permeable, but metabolically stable, diamines was identified.
由于与不良神经影响有关，氯喹的临床应用价值已经降低。需要更好耐受的替代品。本研究的目的是确定与氯喹一样有效但具有不易透过血脑屏障的理化特性的先导化合物。
合成了一系列非哌啶类氯喹类似物的药物样文库。这些化合物在结构和理化性质上具有多样性。它们在适当的体外测定中进行了筛选，并根据其作为先导化合物的潜力进行了评估。评估了特定结构属性和理化性质与活性的相关性。
最有效的类似物是低分子量的未共轭仲胺，其侧链中没有杂原子。然而，这些化合物比氯喹更易代谢和渗透。就理化性质而言，较低的极性表面积、较低的分子量、更多的可旋转键和较少的氢键受体与更高的效力相关。活性与 LogP、LogD 或氢键供体（HBDs）的数量之间没有这种关系。在侧链中添加一个氢键供体得到了一系列活性的二胺，它们与氯喹一样代谢稳定，但渗透性降低。
合成了一系列非哌啶类氯喹类似物的药物样文库。从这个文库中，确定了一个活性先导系列，即不易渗透但代谢稳定的二胺。
