Chemical and Antiplasmodial Investigations on Eremophila -Derived Alkaloids and Semisynthetic Ether Analogues.

Microthecaline A ( 1 ), the known antiplasmodial quinoline serrulatane alkaloid from the roots of Eremophila microtheca F. Muell. ex Benth. (Scrophulariaceae), was targeted for isolation and subsequent use in the generation of a semisynthetic ether library. A large-scale extraction and isolation yielded the previously undescribed quinoline serrulatane microthecaline B ( 2 ), along with crystalline 1 that enabled the first X-ray crystallographic analysis to be undertaken on this rare alkaloid structure class. The X-ray diffraction analysis of 1 supported the absolute configuration assignment of microthecaline A, which was originally assigned by ECD data analysis. Microthecaline A ( 1 ) was converted into 10 new semisynthetic ether derivatives ( 3 - 12 ) using a diverse series of commercially available alkyl halides. Chemical structures of the new serrulatane alkaloid and semisynthetic ether analogues were assigned by spectroscopic and spectrometric analyses. Antiplasmodial evaluations of 1 - 12 showed that the semisynthetic derivative 5 elicited the most potent activity with an IC 50 value of 7.2 μM against Plasmodium falciparum 3D7 (drug-sensitive) strain.