K. Iwasa et al., Structure-activity relationships of quaternary protoberberine alkaloids having an antimalarial activity, EUR J MED C, 34(12), 1999, pp. 1077-1083
Seventeen quaternary protoberberine alkaloids related to berberine I were t
ested for antimalarial activity in vitro against Plasmodium falciparum and
structure-activity relationships are proposed. The activity of the protober
berine alkaloids was influenced by the type of the oxygen substituents on r
ings A, C and D and the position of the oxygen functions on ring D. The pos
ition of the oxygen functions on ring D and the type of the oxygen substitu
ents at the C-13 position (ring C) strongly influenced the activity. Shifti
ng the oxygen functions at C-9 and C-10 to C-10 and C-Il on ring D resulted
in a significant increase in the activity. Compounds bearing a methylenedi
oxy function at C-2 and C-3 (ring A) or C-9 and C-IO (ring D) showed higher
activity than those which have methoxy groups at the same positions. Intro
duction of a methoxy group into the C-l position (ring A) decreased the act
ivity. Replacement of a hydroxy group at C-2 or C-3 (ring A) by a methoxy g
roup led to a reduction in the activity. Displacement of a hydroxy function
at C-13 (ring C) by the oxygen substituents such as OMe, Oft, OCOOEt, and
OCON(Me)(2) reduced the activity. In the same replacement at C-9 (ring D),
the activity depended upon the type of the oxygen function. Six protoberber
ines displayed more potent activity than berberine 1. The activity decrease
d in the order: 10, 11, 17 and 18 > 7 and 8 > 1. (C) 1999 Editions scientif
iques et medicales Elsevier SAS.