Insights into the mechanism of action of ferroquine. Relationship between physicochemical properties and antiplasmodial activity
Insights into the mechanism of action of ferroquine. Relationship between physicochemical properties and antiplasmodial activity
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DOI：
10.1021/mp0500061
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发表时间：
2005-05-01
影响因子：
4.9
通讯作者：
Egan, Timothy J.
中科院分区：
文献类型：
--
作者：
Biot, Christophe;Taramelli, Donatella;Egan, Timothy J.
Ferroquine（FC）是一种4-氨基喹啉类抗疟药，其结构与氯喹相似，但在其侧链上含有一个新的二茂铁基团。以前的工作已经证明，这种化合物在体外和体内对疟疾寄生虫都具有优异的活性，特别是对氯喹抗性寄生虫具有良好的活性，但其作用机制的细节以前尚未报道。在这项研究中，我们已经调查了FQ的物理化学性质与氯喹（CQ）进行比较。与CQ一样，FQ在溶液中与血红素形成复合物（log K = 4.95 +/- 0.05）。FQ是比CQ更强的β-高铁血红素形成抑制剂（相对于高铁血红素，FQ的IC 50 = 0.78当量，CQ为1.9当量）。这些数据表明，FQ的作用机制可能与CQ相似，可能涉及作为药物靶点的血红素和对疟原虫色素形成的抑制。然而，FO的碱性和亲脂性与CO的显著不同。FQ和CQ的亲脂性在假定的食物液泡pH为5.2时质子化时相似（log D分别为-0.77和-1.2），但在pH为7.4时显著不同（log D分别为2.95和0.85）。此外，FQ的pK（a）值（pK（a1）= 8.19和pK（a2）= 6.99）低于CQ的pK（a）值（分别为10.03和7.94）。这表明，将有一定程度上较少的空泡积累的FO相比，CO。FQ的单晶结构测定表明，存在一个强大的内部氢键之间的4-氨基基团和末端N原子。这与二茂铁部分的供电子性质一起，可能解释了降低的pK（a）。有趣的是，该化合物碱性较低引起的蓄积减少部分被其较强的β-血红素抑制作用所补偿。增加亲油性，几何和电子结构的差异，以及在FQ中的N-N距离的变化相比，CQ可能解释其对CO抗性寄生虫的活性。
Ferroquine (FC) is a 4-aminoquinoline antimalarial which contains a quinoline nucleus similar to chloroquine, but a novel ferrocenic group in its side chain. Previous work has demonstrated that this compound has excellent activity against malaria parasites, both in vitro and in vivo, with especially good activity against chloroquine-resistant parasites, but details of its mechanism of action have not previously been reported. In this study, we have investigated the physicochemical properties of FQ for comparison with chloroquine (CQ). Like CQ, FQ forms complexes with hematin in solution (log K = 4.95 +/- 0.05). FQ is an even stronger inhibitor of beta-hematin formation than CQ (IC50 = 0.78 equiv relative to hematin for FQ vs 1.9 for CQ). These data suggest that the mechanism of action of FQ is likely to be similar to that of CQ and probably involves hematin as the drug target and inhibition of hemozoin formation. However, both the basicity and lipophilicity of FO are significantly different from those of CO. The lipophilicity of FQ and CQ are similar when protonated at the putative food vacuole pH of 5.2 (log D = -0.77 and -1.2 respectively), but differ markedly at pH 7.4 (log D = 2.95 and 0.85 respectively). In addition, the pK(a) values of FQ are lower (pK(a1) = 8.19 and pK(a2) = 6.99) than those of CQ (10.03 and 7.94, respectively). This suggests that there will be somewhat less vacuolar accumulation of FO compared with CO. Single crystal structure determination of FQ shows the presence of a strong internal hydrogen bond between the 4-amino group and the terminal N atom. This, together with the electron donating properties of the ferrocene moiety, probably explains the decreased pK(a). Interestingly, the decreased accumulation arising from the less basic behavior of this compound is partly compensated for by its stronger beta-hematin inhibition. Increased lipophilicity, differences in geometric and electronic structure, and changes in the N-N distances in FQ compared to CQ probably explain its activity against CO-resistant parasites.