Rapid and Systematic Exploration of Chemical Space Relevant to Artemisinins: Anti-malarial Activities of Skeletally Diversified Tetracyclic Peroxides and 6-Aza-artemisinins

Abstract

To achieve both structural changes and rapid synthesis of the tetracyclic scaffold relevant to artemisinins, we explored two kinds of de novo synthetic approaches that generate both skeletally diversified tetracyclic peroxides and 6-aza-artemisinins. The anti-malarial activities of the tetracyclic peroxides with distinct skeletal arrays, however, were moderate and far inferior to artemisinins. Given the privileged scaffold of artemisinins, we next envisioned element implantation at the C6 position with a nitrogen without the trimmings of substituents and functional groups. This molecular design allowed the deep-seated structural modification of the hitherto unexplored cyclohexane moiety (C-ring) while keeping the three-dimensional structure of artemisinins. Notably, this approach induced dramatic changes of retrosynthetic transforms that allow an expeditious catalytic asymmetric synthesis with generation of substitutional variations at three sites (N6, C9, and C3) of the 6-aza-artemisinins. These de novo synthetic approaches led to the lead discovery with substantial intensification of the in vivo activities, which undermine the prevailing notion that the C-ring of artemisinins appears to be merely a structural unit but to be a functional area as the anti-malarial pharmacophore. Furthermore, we unexpectedly found that racemic 6-aza-artemisinin (33) exerted exceedingly potent in vivo efficacies superior to the chiral one and the first-line drug, artesunate.

Access to Artemisinin–Triazole Antimalarials via Organo-Click Reaction: High In Vitro/In Vivo Activity against Multi-Drug-Resistant Malaria Parasites

“…This resulted in the discovery of compounds of enhanced in vitro antimalarial potency and in vivo efficacy compared to ART. These observations align with the fact that changes in the skeleton and implantation of chemical motifs surrounding the trioxane warhead can modulate the pharmacological activity of ARTs. − More specifically, these structural changes in the endoperoxide drugs can directly impact the speed of heme-mediated peroxide activation and, subsequently, in the protein alkylation profile. − …”

A New Catalytic Method for the Synthesis of Cyclic Azaperoxides with High Cytotoxic Activity

“…[37,40,57] Like many natural and synthetic peroxide compounds, azaperoxides exhibit various biological activities, including antiparasitic and antitumor activities. [58][59][60] The isolation of artemisinin (qinghaosu), the natural sesquiterpene peroxy lactone, from the plant Artemisia annua (sweet wormwood) and identification of its high antimalarial activity were the events that crucially changed many views on peroxides and their role in medicine and biology. [61] Artemisinin has a relatively high antimalarial activity and a very interesting and unique mechanism of action.…”

Antimalarial and anticancer properties of artesunate and other artemisinins: current development

“…The study has found that deoxyartemisinins that lack an endoperoxide bridge, have no ROS production effect in malarial mitochondria, while artemisinins are distributed in malarial mitochondria and impaired their functions [24]. Bonepally et al studied by synthesizing tetracyclic peroxide and 6-aza-artemisinins and found that moderate to almost negligible anti-malarial activities in the modification of skeletal arrays, functional groups, and the peroxide bridge [25].…”