Unravelling the Structure of Peroxides with Antiparasitic Activity: The Relative Impact of a Trioxolane or a Tetraoxane Pharmacophore on the Overall Molecular Structure

Abstract

Plasmodium falciparum artemisinin‐resistance boosted the quest for novel plasmodial “fast killers,” uncovering antimalarial candidates OZ439 and E209, whose peroxide precursors are 1,2,4‐trioxolane (1) and 1,2,4,5‐tetraoxane (2), differing solely in the pharmacophore (trioxolane or tetraoxane). Combining X‐ray crystallography and vibrational spectroscopy, along with Hirshfeld surface analysis and calculations (CE‐B3LYP/6‐31G(d,p)) of pairwise interaction energies of intermolecular contacts existing in the crystal structure, may deepen the understanding of relative reactivity and properties of these endoperoxides classes. In the crystal, the tetraoxane ring in 2 and the trioxolane‐adamantyl fragment in 1 are disordered, with molecules 1 and 2 existing as two distinct, stable conformations. Whereas the dominant C−H⋅⋅⋅O H‐bonds in 1 connect an adamantyl C−H and O1 or O2 of the trioxolane ring, in 2 they involve the carbonyl oxygen, acting as a double acceptor from phenyl ring C−H groups. C−H⋅⋅⋅O and C−H⋅⋅⋅π H‐bonds define the molecular packing of 2, while C−H⋅⋅⋅H−C van der Waals interactions determine the packing of 1. The dispersive component dominates the interaction energies calculated for the most representative molecular pairs.

An overview on the antimalarial activity of 1,2,4‐trioxanes, 1,2,4‐trioxolanes and 1,2,4,5‐tetraoxanes

“…236 Patricia et al in 2022 have resolved the structure of peroxides (OZ439 and E209) with antiparasitic activity and found the effect of trioxolane on the overall molecular structure. 237 Moreover, OZ439 4b showed excellent effectiveness in mice which were infected with P. berghei at a singular dosage of 20 mg/kg PO, as well as substantial improvement in pharmacokinetic characteristics. 238,239 Vennerstrom's research team conducted a comprehensive SAR study on various OZ439 4b compounds in 2017, concluding that as compared to tertiary amino-ozonides the primary and secondary amino-ozonides are metabolically more stable as well as have a higher water solubility.…”

“…OZ439 4b accomplished the 2nd round of the study effectively and functioned as a fast‐acting medication throughout the erythrocytic phases of asexual P. falciparum 236 . Patricia et al in 2022 have resolved the structure of peroxides (OZ439 and E209) with antiparasitic activity and found the effect of trioxolane on the overall molecular structure 237 . Moreover, OZ439 4b showed excellent effectiveness in mice which were infected with P. berghei at a singular dosage of 20 mg/kg PO, as well as substantial improvement in pharmacokinetic characteristics 238,239 .…”