Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
J Med Chem. 2013 Feb 28;56(4):1596-613. doi: 10.1021/jm301422h. Epub 2013 Feb 14.
Five compounds displaying an unprecedented binding mode of chloroquine to ferrocene through the bridging of the cyclopentadienyl rings were studied alongside their monosubstituted ferrocene analogues and organic fragments. The antiplasmodial activity was evaluated against strains of the malaria parasite (Plasmodium falciparum). While the chloroquine-bridged ferrocenyl derivatives were less active than their five monosubstituted ferrocenyl analogues, they retained activity in the drug-resistant strains. The biological and physical properties were correlated to antiplasmodial activity. Intramolecular hydrogen bonding was associated with increased antiplasmodial action, but it is not the determining factor. Instead, balance between lipophilicity and hydrophilicity had a greater influence. It was found that calculated partition coefficient (log P) values of 4.5-5.0 and topological polar surfaces area (tPSA) values of ∼26.0 Å(2) give the best balance. The particular conformation, compact size, and lipophilicity/hydrophilicity balance observed in the bridged compounds provide them with the structural characteristics needed to escape the mechanisms responsible for resistance.
研究了五种通过桥连环戊二烯环使氯喹与二茂铁结合的前所未有的结合模式的化合物，以及它们的单取代二茂铁类似物和有机片段。评估了它们对疟原虫（恶性疟原虫）菌株的抗疟活性。虽然氯喹桥连二茂铁衍生物的活性不如它们的五个单取代二茂铁类似物，但它们在耐药菌株中仍保持活性。生物和物理性质与抗疟活性相关。分子内氢键与增加的抗疟作用相关，但不是决定性因素。相反，亲脂性和亲水性之间的平衡有更大的影响。发现计算的分配系数（log P）值为 4.5-5.0 和拓扑极性表面积（tPSA）值为∼26.0 Å（2）可获得最佳平衡。桥连化合物中观察到的特定构象、紧凑尺寸和亲脂性/亲水性平衡为它们提供了逃避耐药机制所需的结构特征。
