Manzamines antimalarial activity

The activity of manzamine Y against both the D 6 clone and W2 clone of the malarial parasite P. falciparum (IC50 420 and850 ng/mL, respectively) is significantly lower than that of 8-hydroxymanzamine A (IC50 6.0 and 8.0 ng/mL, respectively). This difference indicates that the change of the hydroxyl substitution from the C-8 position of the (3-carboline moiety to the C-6 position decreases the antimalarial activity dramatically. 

Additional information on structure-activity relationships came with the isolation of neo-kauluamine [33, Fig. (8)] a very complex molecule constituted by two manzamine units dimerized through ether linkages between the eight-membered rings [45], Although also this molecule, like manzamine F (32), lacks the double bond in the eight-membered ring, it demonstrated to possess the same antimalarial activity of manzamine A. 

The lack of antimalarial activity for 12,34-oxamanzamine A [34, Fig. (8)] (IC50 = 5000 ng/mL) [42] indicates that the C-12 hydroxy, the C-34 methine or the conformation of the eight-membered ring are of key importance for the antimalarial activity. Authors proposed that these data, combined to the lack of activity of manzamine F, suggest that the ability of the C-34 allylic carbon to form a stabilized carbocation may play a... 

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