The delivery of drugs to the brain is complicated by the multiple factors including low blood-brain barrier (BBB) passive permeability, active BBB efflux systems, and plasma protein binding. Thus, a detailed understanding of the transport of the new potent substances through the membranes is vitally important and their physico-chemical characteristics should be analyzed at first. This work presents an evaluation of drug likeness of eight 7-O-arylpiperazinylcoumarin derivatives with high affinity towards serotoninergic receptors 5-HT1A and 5-HT2A with particular analysis of the requirements for the CNS chemotherapeutics. The binding constants to human serum albumin (HSA) were determined at physiological pH using fluorescence spectroscopy, and then their mode of action was explained by analysis of theoretical HSA complexes. Dynamic simulation of systems allowed for reliable evaluation of the interaction strength. The analyzed coumarins were able to pass BBB, and they present good drug likeness properties. They showed high affinities to HSA (log KQ = 5.3-6.0 which corresponds to -8.12 to -7.15 kcalmol-1 of Gibbs free energy). The changes of the emission intensity upon binding to HSA were scrutinized showing the different mode of action for 4-phenylpiperazinylcoumarins. The values of computed Gibbs free energy and determined on the basis of experimentally obtained binding constants log KQ coincide suggesting a good quality of the theoretical model. Overall the 8-acetyl-7-O-arylpiperazinyl-4-methylcoumarin derivatives represent valuable lead compounds to be further tested in various preclinical assays as a possible chemotherapeutics against CNS diseases. Studied coumarins can be metabolized by cytochrome P450 to aldehydes and hydroxy derivatives. The existence of other binding sites inside HSA than Sudlow's site 1 was postulated. The longer aliphatic linker between coumarin and piperazine moieties favored binding to HSA in other than Sudlow site 1 pocket.

中文翻译：

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评估血脑屏障渗透性和检查与7-O-芳基哌嗪基香豆素作为潜在抗精神病药物的人血清白蛋白的结合。

多种因素使药物向大脑的输送变得复杂，包括低血脑屏障（BBB）被动渗透性，主动BBB外排系统和血浆蛋白结合。因此，对新的有效物质通过膜的运输的详细了解至关重要，因此首先应分析其理化特性。这项工作提出了对对5-羟色胺能受体5-HT1A和5-HT2A具有高亲和力的8种7-O-芳基哌嗪基香豆素衍生物的药物相似性评估，并特别分析了中枢神经系统化学疗法的需求。使用荧光光谱法在生理pH下确定与人血清白蛋白（HSA）的结合常数，然后通过理论HSA配合物的分析解释其作用方式。系统的动态仿真可以可靠地评估相互作用强度。分析的香豆素能够通过BBB，并且具有良好的药物相似性。他们显示出对HSA的高度亲和力（log KQ = 5.3-6.0，对应于Gibbs自由能的-8.12至-7.15 kcalmol-1）。仔细研究了与HSA结合后的发射强度变化，显示了4-苯基哌嗪基香豆素的不同作用方式。基于实验获得的结合常数log KQ确定的计算吉布斯自由能的值一致，这表明理论模型的质量很高。总体而言，8-乙酰基-7-O-芳基哌嗪基-4-甲基香豆素衍生物是有价值的先导化合物，将在各种临床前测定中进一步测试，作为可能的抗CNS疾病的化学治疗方法。研究的香豆素可被细胞色素P450代谢为醛和羟基衍生物。假设HSA内部除Sudlow的位点1外还存在其他结合位点。香豆素和哌嗪部分之间较长的脂肪族连接基有利于与Sudlow位点1口袋以外的HSA结合。