Biot Christophe, Taramelli Donatella, Forfar-Bares Isabelle, Maciejewski Lucien A, Boyce Mlandzeni, Nowogrocki Guy, Brocard Jacques S, Basilico Nicoletta, Olliaro Piero, Egan Timothy J
Laboratoire de Catalyse de Lille-UMR CNRS 8010, ENSCL, Bâtiment C7, Université des Sciences et Technologies, B.P. 90108, 59652, Villeneuve d'Ascq cedex, France.
Mol Pharm. 2005 May-Jun;2(3):185-93. doi: 10.1021/mp0500061.
Ferroquine (FQ) 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 (IC(50) = 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 FQ are significantly different from those of CQ. 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 FQ compared with CQ. 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 CQ-resistant parasites.
非诺喹（FQ）是一种4-氨基喹啉类抗疟药，其含有与氯喹类似的喹啉核，但侧链中有一个新型二茂铁基团。先前的研究表明，该化合物在体外和体内对疟原虫均具有优异的活性，对耐氯喹的疟原虫尤其有效，但此前尚未报道其作用机制的细节。在本研究中，我们研究了FQ的物理化学性质以与氯喹（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对β-血红素形成的抑制作用比CQ更强（相对于血红素，FQ的IC50 = 0.78当量，而CQ为1.9）。这些数据表明，FQ的作用机制可能与CQ相似，可能涉及以血红素作为药物靶点并抑制疟原虫色素的形成。然而，FQ的碱性和亲脂性均与CQ有显著差异。当在假定的食物泡pH值5.2下质子化时，FQ和CQ的亲脂性相似（log D分别为-0.77和-1.2），但在pH 7.4时差异显著（log D分别为2.95和0.85）。此外，FQ的pKa值较低（pKa1 = 8.19，pKa2 = 6.99），低于CQ（分别为10.03和7.94）。这表明与CQ相比，FQ在液泡中的积累会略少。FQ的单晶结构测定表明，4-氨基与末端N原子之间存在强的分子内氢键。这与二茂铁部分的供电子性质一起，可能解释了pKa的降低。有趣的是，该化合物碱性降低导致的积累减少部分被其更强的β-血红素抑制作用所补偿。与CQ相比，FQ亲脂性增加、几何和电子结构不同以及N-N距离变化可能解释了其对耐CQ疟原虫的活性。
