K. Iwasa et al., ANTIMALARIAL ACTIVITY AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF PROTOBERBERINE ALKALOIDS, European journal of medicinal chemistry, 33(1), 1998, pp. 65-69
The thirty-nine protoberberine derivatives including berberine 1 and p
almatine 2 were tested for antimalarial activity in vitro against Plas
modium falciparum and structure-activity relationships are proposed. T
he activity of the protoberberine alkaloids was influenced by the type
of the quaternary nitrogen atom, the nature and the size of the subst
ituents at the C-13 position, and the type of O-alkyl substituents on
rings A and D. The activity of the quaternary protoberberinium salts w
ith an aromatic ring C such as berberine was higher than that of the q
uaternary salts such as the N-metho salts or the N-oxides of tetrahydr
o and dihydro derivatives as well as tertiary tetrahydroprotoberberine
s. Of the 13-alkyl derivatives of 1 and 2, the activity did not always
increase as the length of the aliphatic chain rose in the order methy
l, ethyl, propyl, butyl, and hexyl group. 13-Butylberberine (1Bu) and
13-propylpalmatine (2Pr) were the most active compounds among the 13-a
lkylberberines and 13-alkylpalmatines, respectively. 13-Hydroxyberberi
ne 3 possessed the same level of activity as 1. Of 1 and 2 with differ
ent substituents types on Ring A, the activity of 1 was significantly
higher than that of 2. Among berberrubines 4 and 5 and their C-9-O-alk
yl derivatives 6 and 7, the activity of 9-O-ethylberbermbine 6 was the
highest. Of the potent protoberberinium salts, the activity decreased
in the order: 1, 3 > 2Pr > 6 > 1Bu. A positive effect on the activity
might be exerted by the introduction of a more hydrophilic function i
nto the C-13 position of the protoberberinium salts. (C) Elsevier, Par
is.