Non-reductive Homolytic Scission of Endoperoxide Bond for Activation of Artemisinin: The Bi-radical Perspectives

Abstract

<p>Artemisinin is the most famous antimalarial drug against malaria caused by <i>Plasmodium falciparum</i>. 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 <i>ab initio</i> 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. Here adopting the CDFT 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 clearly 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. </p>

Quantum Interference and Spin Filtering Effects in Photo-responsive Endoperoxide Based Single Molecular Device

“…19 The likely existence of a diradical intermediate reachable by the photoactivation of EPO ground state is unambiguously reported and has been exploited for numerous photobiological processes including selective destruction of cancer cells and activation of anti-malarial drugs. [20][21][22] Besides this, EPOs also stand out as the chemical source of singlet oxygen storing systems where it enters another competing cycloreversion pathway to parent acenes via the cleavage of C-O bond. 23 Despite their obvious appeal as spin polarized candidates, EPOs have seldom been used in molecular spintronics.…”