Non-reductive Homolytic Scission of Endoperoxide Bond for Activation of
Artemisinin: The Bi-radical Perspectives
Abstract
Artemisinin is the most successful antimalarial drug against malaria
caused by Plasmodium falciparum. Despite its tremendous success
and popularity in malaria therapeutics, the molecular mechanism of
artemisinin’s activity is still elusive. The activation of artemisinin,
i.e., cleavage of the endoperoxide bond at the infected cell that
generates radical intermediates and the subsequent chemical
rearrangements plays a key role in the antimalarial activities. In this
work, applying state-of-the-art computational techniques based on the
spin-constraint density functional theory (CDFT) along with ab
initio thermodynamics, we have investigated various key steps of the
molecular mechanism of artemisinin. The well-accepted artemisinin
activation process is the reductive heterolytic scission of the
endo-peroxide bond which is followed by subsequent chemical reactions
that propagate via mono-radical intermediates. Adopting CDFT
methodology, here we have investigated the possible alternative
‘biradical’ intermediates and their mechanistic pathways for the
subsequent chemical reactions. The change in Gibbs free energy
associated with the activation of artemisinin through
homolytic-scissoring (biradical) intermediate is quite competitive and
favorable compared to the reductive heterolytic-scissoring (monoradical)
process. This indicates the alternative possibilities for the biradical
activation process. The reported experimental EPR signals for the
biradicals especially for similar anti-malarial drugs like G3-factor
support our observations.