Structure-activity relationships of the antimalarial agent artemisinin and the research progress on the artemisinin analogues with novel pharmacological actions

Abstract

Artemisinin is a sesquiterpene lactone compound containing a peroxy bridge structure, extracted from Compositae Artemisia annua L. in 1971. Discovered by Chinese researchers, artemisinin and its derivatives are currently the most effective drugs in the world for the treatment of chloroquine-resistant Plasmodium falciparumstrains and cerebral malaria. As first-line antimalarial medicines, artemisinin and its derivatives have saved millions of lives, and artemisinin has been reputed as “the best hope for malaria treatment” by World Health Organization. At Nobel Prize Award Ceremony in 2015, Tu Youyou, a natural product medicinal chemist at the China Academy of Chinese Medical Sciences who made significant contribution to the discovery of artemisinin as an antimalarial drug, delivered a speech entitled “Artemisinin—A gift from traditional Chinese medicine to the world”. Tu said: “From research experience gained from artemisinin discovery, we learnt strengths of both Chinese and Western medicines. There is great potential and future advances if these strengths can be fully integrated. We have a substantial amount of natural resource from which our fellow medical researchers can develop novel medicines”. Doubtless the discovery of artemisinin represents a banner in the history of Chinese pharmaceutical industry, which is of immense significance both to enlighten the currently much modernized drug discovery world and to encourage young generations of scientists working with the traditional Chinese medicines. In order to understand the antimalarial mechanism of artemisinin analogues, we firstly discussed on quantitative structure- activity relationship, structure-based physico-chemical properties, and molecular docking generated putative “bioactive” conformations of artemisinin analogues. In addition to the outstanding antimalarial activity, artemisinin and its derivatives also show significant immunosuppressive effects both in vitro and in vivo . We then summarized some typical artemisinin analogues that exhibit promising therapeutic effects on multiple autoimmune diseases, by suppressing the differentiation and expansion of pathologic T helper cells and accumulation of plasma cells, etc. The unusual endoperoxide and multiple cyclic structure of artemisinin has also been extensively explored to develop analogues with cytotoxic anticancer effects. Unfortunately, most of these artemisinin analogues failed to show tumor growth inhibition in vivo . To overcome this limitation, we finally reviewed some recent progresses to develop molecularly targeted anticancer therapies derived from artemisinin, by combining the typical skeleton of artemisinin or its fragmented intermediates with a molecularly targeted drug bullet. Among several tried approaches, the incorporation of a Smo antagonistic structural motif into the structure of artemisinin led to highly potent Smo-targeting antagonists. The recognition by the Nobel Prize does not mean that the study of artemisinin is over; instead, this great honor will inspire scientists around the world to move on to discover more therapeutic effects of artemisinin compounds, and to explore other potential gifts from Traditional Chinese Medicine.