TY - JOUR
T1 - Iron-mediated degradation kinetics of substituted dispiro-1,2,4-trioxolane antimalarials
AU - Creek, Darren John
AU - Charman, William Neil
AU - Chiu, Francis Chi Keung
AU - Prankerd, Richard John
AU - McCullough, Kevin J
AU - Dong, Yuxiang
AU - Vennerstrom, Jonathan
AU - Charman, Susan Ann
PY - 2007
Y1 - 2007
N2 - The iron-mediated reactivity of various dispiro-1,2,4-trioxolanes was determined by automated kinetic analyisis under standard reaction conditions. The active antimalarial compounds underwent peroxide bond cleavage by Fe(II) resulting in products indicative of carbon-centered radical formation. The rate of reaction was heavily influenced by the presence of spiro-substituted adamantane and cyclohexane rings, and was also significantly affected by cyclohexane ring substitution. Steric hindrance around the peroxide oxygen atoms appeared to be the major determinant of reaction rate, however polar substituents also affected reactivity by an independent mechanism. A wide range of reaction rates was observed within this class of peroxide antimalarials, however iron-mediated reactivity did not directly correlate with in vitro antimalrial activity.
AB - The iron-mediated reactivity of various dispiro-1,2,4-trioxolanes was determined by automated kinetic analyisis under standard reaction conditions. The active antimalarial compounds underwent peroxide bond cleavage by Fe(II) resulting in products indicative of carbon-centered radical formation. The rate of reaction was heavily influenced by the presence of spiro-substituted adamantane and cyclohexane rings, and was also significantly affected by cyclohexane ring substitution. Steric hindrance around the peroxide oxygen atoms appeared to be the major determinant of reaction rate, however polar substituents also affected reactivity by an independent mechanism. A wide range of reaction rates was observed within this class of peroxide antimalarials, however iron-mediated reactivity did not directly correlate with in vitro antimalrial activity.
UR - http://www3.interscience.wiley.com/cgi-bin/jhome/68503813?CRETRY=1&SRETRY=0
M3 - Article
SN - 0022-3549
VL - 96
SP - 2945
EP - 2956
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
IS - 11
ER -