Amaryllidaceae alkaloids from Hippeastrum X Hybridum CV. Ferrari, and preparation of vittatine derivatives as potential ligands for Alzheimer´s disease

Abstract

Fourteen (1–14) known Amaryllidaceae alkaloids, of various structural types, have been isolated from fresh bulbs of Hippeastrum X hybridum cv. Ferrari. The chemical structures were identified by various spectroscopic (1D and 2D NMR) and mass spectrometric (GC–MS, LC-MS) methods, and by comparison with literature data. Isolated alkaloids which, up to this date have not been studied for their inhibition potency against AChE, BuChE and POP, were screened in vitro for these inhibition activities. Unfortunatelly, all natural alkaloids were inactive in the AChE/BuChE assay; only zephyranthine (14) displayed moderate inhibition activity agains POP with an IC50 value of 142 ± 10 µM. Moreover, twelve new derivatives of the haemanthamine-type alkaloid vittatine (7), isolated in gram amounts from Hippeastrum cv. Ferrari, have been designed, synthesized and tested in vitro with particular emphasis on the treatment of neurodegenerative diseases. Some of the tested compounds revealed an intriguing selective hBuChE inhibitory profile with single-digit micromolar IC50 values. The strongest hBuChE inhibition was demonstrated by 3-O-(2-methylbenzoyl)vittatine (7b), 3-O-(2-nitrobenzoyl)vittatine (7h) and 3-O-(2-chlorbenzoyl)vittatine (7m) with IC50 values 8.0 ± 0.1 µM, 1.4 ± 0.1 µM and 5.4 ± 0.1 µM, respectively. The mode of hBuChE inhibition was minutely inspected using enzyme kinetic analysis in tandem with in silico experiments, the latter elucidating crucial interaction in 7b-, 7h-, and 7m-hBuChE complexes.