Perry Christine S, Charman Susan A, Prankerd Richard J, Chiu Francis C K, Dong Yuxiang, Vennerstrom Jonathan L, Charman William N
Centre for Drug Candidate Optimisation, Victorian College of Pharmacy, Monash University, Parkville Campus, Victoria 3052, Australia.
J Pharm Sci. 2006 Apr;95(4):737-47. doi: 10.1002/jps.20568.
Chemical stability of a new class of ozonide (1,2,4 trioxolanes) antimalarial compounds was investigated. The effects of pH, ionic strength, dielectric constant and cyclodextrin-complexation on the chemical stability and degradation product formation of selected compounds were examined. The mechanism of degradation in aqueous solution was probed using (18)O-labelled water and kinetic solvent isotope effect studies. The effect of stereochemistry was investigated using selected pairs of stereoisomers. The degradation of the ozonides in aqueous solution followed apparent first-order kinetics, with no effect of ionic strength and no indication of any direct involvement of water in the degradation mechanism. All major degradation products were identified and mass balance was confirmed. Stereochemistry had a significant effect on degradation rate; trans isomers degrading approximately four-fold faster than the corresponding cis isomers. The degradation rates were essentially independent of pH above pH 2; however, an additional specific acid catalysed pathway was dominant below pH 2. Solvent dielectric constant had a significant effect on the degradation rate. It is proposed that the degradation observed in aqueous solution occurred through a concerted heterolytic scission of the central ozonide ring, with chemical substituents on the cyclohexyl ring having only a minor influence on degradation rate.
研究了一类新型臭氧化物（1,2,4-三氧杂环戊烷）抗疟化合物的化学稳定性。考察了pH、离子强度、介电常数和环糊精络合对所选化合物化学稳定性及降解产物形成的影响。利用（18）O标记水和动力学溶剂同位素效应研究探究了水溶液中的降解机理。使用选定的立体异构体对研究了立体化学的影响。臭氧化物在水溶液中的降解遵循表观一级动力学，离子强度无影响，且没有迹象表明水直接参与降解机理。鉴定了所有主要降解产物并确认了质量平衡。立体化学对降解速率有显著影响；反式异构体的降解速度比相应的顺式异构体快约四倍。在pH高于2时，降解速率基本与pH无关；然而，在pH低于2时，另一条特定的酸催化途径占主导。溶剂介电常数对降解速率有显著影响。有人提出，在水溶液中观察到的降解是通过中心臭氧化物环的协同异裂发生的，环己基环上的化学取代基对降解速率的影响较小。
