GlaxoSmithKline Research Centre Zagreb Ltd., Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia.
Eur J Pharm Sci. 2013 May 13;49(2):206-19. doi: 10.1016/j.ejps.2013.02.019. Epub 2013 Mar 7.
Macrolones are a new class of antimicrobial compounds consisting of a macrolide scaffold linked to a 4-quinolone-3-carboxylic acid moiety via C(4″) position of a macrolide. As macrolides are known to possess favorable pharmacokinetic properties by accumulating in inflammatory cells, in this study we determined the intensity of accumulation in human polymorphonuclear leukocytes (PMNs) of 57 compounds of the macrolone class and analyzed the relationship between the molecular structure and this cellular pharmacokinetic property. Accumulation of macrolones ranged from 0 to 5.5-fold higher than the standard macrolide azithromycin. Distinct structural features in all three considered molecule parts: the macrolide scaffold, quinolone moiety and the linker, affect cellular accumulation. Interestingly, while the parent macrolide, azithromycin, accumulates approximately 3-fold more than clarithromycin, among macrolones all clarithromycin derivatives accumulated in PMNs significantly more than their azithromycin counterparts. Modeling cellular accumulation of macrolones with simple molecular descriptors, as well as with the measured octanol-water distribution coefficient, revealed that the number of hydrogen bond donors and secondary amide groups negatively contribute to macrolone accumulation, while lipophilicity makes a positive contribution.
大环内酯类是一类新型的抗菌化合物，由大环内酯通过 C(4″)位与 4-喹诺酮-3-羧酸部分连接而成。由于大环内酯类药物已知通过在炎症细胞中积累而具有良好的药代动力学特性，在本研究中，我们测定了 57 种大环内酯类化合物在人多形核白细胞（PMN）中的积累强度，并分析了分子结构与这种细胞药代动力学特性之间的关系。大环内酯类化合物的积累强度比标准大环内酯类药物阿奇霉素高 0 至 5.5 倍。在所有三个考虑的分子部分：大环内酯骨架、喹诺酮部分和连接体中，都存在明显的结构特征，影响细胞积累。有趣的是，虽然母体大环内酯类药物阿奇霉素的积累量比克拉霉素高约 3 倍，但在大环内酯类化合物中，所有克拉霉素衍生物在 PMN 中的积累量都明显高于其阿奇霉素对应物。用简单的分子描述符和测定的辛醇-水分配系数对大环内酯类化合物的细胞积累进行建模，表明氢键供体和仲酰胺基团的数量对大环内酯类化合物的积累有负面影响，而亲脂性则有正面影响。
