Creek Darren J, Chalmers David K, Charman William N, Duke Brian J
Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.
J Mol Graph Model. 2008 Oct;27(3):394-400. doi: 10.1016/j.jmgm.2008.06.008. Epub 2008 Jul 9.
Quantum chemical methods were used to obtain a structure for the peroxide-iron intermediate complex required for the inner-sphere reduction of dispiro-1,2,4-trioxolane antimalarials. Investigation of this biologically important interaction with iron(II) allows further understanding of the mechanisms of action and clearance of this promising new class of fully synthetic peroxide antimalarials. UHF, B3LYP and B3LYP//MP2 calculations were undertaken to provide structural and energetic information about the coordination complex of iron(II) with five representative trioxolanes, ranging in both iron-mediated reactivity and antimalarial activity. Significant energy differences were observed between the conformational isomers of these trioxolanes, indicating the importance of steric interactions between the iron complex ligands and the trioxolane substituents. These calculations may explain the slower iron-mediated reaction rates of trioxolanes that preferentially adopt a conformation that sterically shields the peroxide bond. The relationship between antimalarial activity and accessibility of the peroxide bond to iron has also been demonstrated for these trioxolanes.
采用量子化学方法获得了双螺-1,2,4-三氧戊环抗疟药内球还原所需的过氧化物-铁中间体配合物的结构。对这种与铁（II）的生物学重要相互作用的研究有助于进一步了解这类有前景的新型全合成过氧化物抗疟药的作用机制和清除机制。进行了UHF、B3LYP和B3LYP//MP2计算，以提供关于铁（II）与五种代表性三氧戊环的配位配合物的结构和能量信息，这些三氧戊环在铁介导的反应性和抗疟活性方面各不相同。在这些三氧戊环的构象异构体之间观察到显著的能量差异，表明铁配合物配体与三氧戊环取代基之间的空间相互作用很重要。这些计算可能解释了那些优先采取构象从而在空间上屏蔽过氧化物键的三氧戊环的铁介导反应速率较慢的原因。对于这些三氧戊环，还证明了抗疟活性与过氧化物键对铁的可及性之间的关系。
