Picomolar antimalarial agent from a Chinese medicinal plant

IMAGE: PICOMOLAR ANTIMALARIAL AGENT FROM A CHINESE MEDICINAL PLANT

CREDIT: ©SCIENCE CHINA PRESS

Dimeric sesquiterpenoids (DS), particularly the dimeric lindenane sesquiterpenoids dimers (DLS), featuring a basic scaffold by a [4 + 2] endo Diels–Alder reaction of two lindenane sesquiterpenoid monomers, are the characteristic components that occur mainly in the Chloranthus and Sarcandragenera. Shizukaol A from Chloranthus japonicus was the first reported DLS, after which over 110 analogues have been discovered. Due to their complex polycyclic architectures with more than 10 stereocenters and significant bioactivities, DLS have gained extensive attention in recently years, especially the numerous efforts toward their total syntheses.

Prof. Jian-min Yue’s research group in Shanghai Institute of Materia Medica has been focusing on the chemical and biological studies of this structural interesting compound class since 2006, which resulted in the discovery of 50 more DS from six species of the two genera. Additionally, inspired by the usage of many Chloranthaceae species as traditional Chinese medicine to treat malaria, they explored the remarkable antimalarial potential of DLS for the first time, and conducted a structural-activity relationship (SAR) study based on a small library of isolated DLS (J. Nat. Prod. 2017, 80, 96–107).

His research group recently carried out a systematic phytochemical study and antimalarial tests on S. glabra subsp. brachystachys to discover more antimalarial DS. In the study, they isolated and characterized seven novel dimeric sesquiterpenoids (1–7) and 14 known analogues (8–21), and further evaluated their antimalarial activities and explored the SARs.

Their study identified compound 3 as the most potent antimalarial agent reported hitherto, exhibiting an EC50 value of 4.3 ± 0.3 pM against the chloroquine-resistant Plasmodium falciparum Dd2, which is about 1000-fold more active than artemisinin. Their study provides a very potent antimalarial drug candidate and/or drug lead, and sheds light on the SAR study and structural modification of DLS as potential antimalarial agents.