Structure-Activity Relationship of 9,10-Anthraquinone Analogues from Rennellia elliptica and Their Antiplasmodial Activity

Anthraquinones isolated from the roots of Rennellia elliptica Korth. demonstrated interesting antiplasmodial activity. The activity however, varies depending on substitution pattern of the anthraquinone skeleton which warrants further investigation. This paper reports preliminary structure-activity relationship of a series of 9,10-anthraquinones and their antiplasmodial activity. The natural anthraquinones were isolated from roots extract of R. elliptica. The analogues of bioactive anthraquinones were synthesized through Friedel-Craft reaction between phthalic anhydride and various benzene derivatives in the presence of eutectic mixture of aluminium chloride and sodium chloride. The antiplasmodial activity was determined based on inhibition of the compounds against Plasmodium falciparum (3D7) growth in vitro. Combination of methyl and hydroxyl substituents at different positions on the anthraquinone skeleton caused strong antiplasmodial activity. The ortho-arranged substituents at 2,3 positions exhibited strongest activity with IC50 value of 0.08µg/ml followed by the compound with substituents at 1,2 positions. The para-arranged (1,4) and meta-arranged (1,3) substituted anthraquinones showed less potent activity. On the other hand, analogues of dihydroxyanthraquinones displayed a reverse order of activity with the strongest inhibition shown by 1,3-dihydroxyanthraquinone. The hydroxy-methyl anthraquinones and dihydroxyanthraquinones substituted with additional methyl group at C-6/C-7 on ring A showed similar pattern of activity but much weaker than those substituted only on ring C. Protection of hydroxyl group via methylation reaction caused significant variation in antiplasmodial activity. Anthraquinones substituted at C-2 and C-3 and anthraquinones substituted at C-1, C-2 and C-6/C-7 promotes antiplasmodial activity. Structural differences due to different substitution pattern affects antiplasmodial activity of 9,10-anthraquinones.

Keywords: Anthraquinones, Antiplasmodial, Structure-Activity Relationship, Rennellia elliptica