An examination of the bulbs of Scilla socialis has resulted in the isolation of 11 hyacinthacines, two pyrrolidines, and three piperidines. The structures of the new alkaloids were elucidated by spectroscopic methods as beta-1-C-ethyldeoxymannojirimycin (5), hyacinthacines B7 (10), C2 (11), C3 (12), C4 (13), and C5 (14), and alpha-5-C-(3-hydroxybutyl)hyacinthacine A2 (15). Although, beta-l-homofuconojirimycin (3) and alpha-7-deoxyhomonojirimycin (alpha-7-deoxy-HNJ, 4) are previously known alkaloids, this is the first report of their occurrence in the plant family Hyacinthaceae. Alkaloid 11 was found to be a good inhibitor of bacterial beta-glucosidase and human placenta alpha-l-fucosidase, with IC50 values of 13 and 17 microM, respectively, while alkaloid 12 showed no inhibitory activity toward alpha-l-fucosidase but was a more potent inhibitor of bovine liver beta-galactosidase (IC50 = 52 microM) than 11. Alkaloids 13 and 14 were shown to be inhibitory toward mammalian alpha-glucosidase (IC50 = 45 and 77 microM, respectively), and alkaloid 14 was demonstrated as a moderate inhibitor of bacterial beta-glucosidase (IC50 = 48 microM).

Two economically and biomedically important platyhelminth species, Fasciola hepatica (liver fluke) and Schistosoma mansoni (blood fluke), are responsible for the neglected tropical diseases (NTDs) fasciolosis and schistosomiasis. Due to the absence of prophylactic vaccines, these NTDs are principally managed by the single class chemotherapies triclabendazole (F. hepatica) and praziquantel (S. mansoni). Unfortunately, liver fluke resistance to triclabendazole has been widely reported and blood fluke insensitivity/resistance to praziquantel has been observed in both laboratory settings as well as in endemic communities. Therefore, the identification of new anthelmintics is necessary for the sustainable control of these NTDs in both animal and human populations. Here, continuing our work with phytochemicals, we isolated ten triterpenoids from the mature bark of Abies species and assessed their anthelmintic activities against F. hepatica and S. mansoni larval and adult lifecycle stages. Full 1H and 13C NMR-mediated structural elucidation of the two most active triterpenoids revealed that a tetracyclic steroid-like nucleus core and a lactone side chain are associated with the observed anthelmintic effects. When compared to representative mammalian cell lines (MDBK and HepG2), the most potent triterpenoid (700015; anthelmintic EC50s range from 0.7 μM–15.6 μM) displayed anthelmintic selectivity (selectivity indices for F. hepatica: 13 for newly excysted juveniles, 46 for immature flukes, 2 for mature flukes; selectivity indices for S. mansoni: 14 for schistosomula, 9 for immature flukes, 4 for adult males and 3 for adult females) and induced severe disruption of surface membranes in both liver and blood flukes. S. mansoni egg production, a process responsible for pathology in schistosomiasis, was also severely inhibited by 700015. Together, our results describe the structural elucidation of a novel broad acting anthelmintic triterpenoid and support further investigations developing this compound into more potent analogues for the control of both fasciolosis and schistosomiasis.

[reaction: see text] A flexible route to polyhydroxylated pyrrolizidine alkaloids is described, starting from commercially available N-Boc pyrrole and using a partial reduction as the key step. Tactics for varying the stereochemistry around the ring by choice of partial reduction conditions are discussed and methods for constructing the bicyclic ring system of the pyrrolizidine targets are examined. Intramolecular S(N)2 type displacement reactions were found to be an efficient way of forming the requisite bicyclo ring systems while iodine-promoted cyclizations proved unsuitable. A first synthesis of hyacinthacine A1 is described that also confirmed the structure of the natural product, and a short stereoselective synthesis of 1-epiaustraline is also discussed in detail.