Cytochrome P450 3A4 Inhibitory Activity Studies within the Lycorine series of Alkaloids

A mini-panel of semi-synthetic analogs of the Amaryllidaceae alkaloid lycorine was screened for cytochrome P450 3A4 (CYP3A4) inhibitory activity, the most potent of which exhibited inhibition as low as 0.21 microM. Elements of this novel pharmacophore unravelled include bulky lipophilic substitution at C2 in conjunction with a small hydrogen bond donor/acceptor at C1, or bulky electron-rich substitution at C1 in conjunction with a vicinal hydrogen bond donor/acceptor.