No abstract

Rennellia elliptica (Rubiaceae) has been used by local Jakun Community in the Endau Rompin State Park for the treatment of jaundice. Previous study has revealed the antiplasmodial activity of the root extract and major anthraquinones isolated from the roots. The present study entails the optimization of extraction methods, qualitative and quantitative analyses of selected marker anthraquinones and in vivo antiplasmodial activity along with toxicity and inhibition of β-hematin in vitro. HPLC profile showed the present of marker compounds as major constituents with content ranging 3-12 µg/g extract. The root extract showed potent antiplasmodial activity against rodent malaria, Plasmodium berghei with ED50 value of 1.23 µg/ml BW. The major anthraquinones, damnacanthal and nordamnacanthal showed significant inhibition against β-hematin formation via lipids and HRP2 catalyses. However, the root extract is slightly toxic against hepatocyte cell. These data suggests that R. elliptica is a potential herbal remedy for malaria treatment and antiplasmodial of the root extract possibly due to the action of major anthraquinones.

Background: A phytochemical study on medicinal plants used for the treatment of fever and malaria in Africa yielded metabolites with potential antiplasmodial activity, many of which are Anthraquinones (AQ). AQs have similar sub-structure as naphthoquinones and xanthones, which were previously reported as novel antiplasmodial agents. </P><P> Objective: The present study aimed to investigate the structural requirements of 9,10- anthraquinones with hydroxy, methoxy and methyl substituents to exert strong antiplasmodial activity and to investigate their possible mode of action. </P><P> Methods: Thirty-one AQs were synthesized through Friedel-Crafts reaction and assayed for antiplasmodial activity in vitro against Plasmodium falciparum (3D7). The selected compounds were tested for toxicity and probed for their mode of action against β-hematin dimerization through HRP2 and lipid catalyses. The most active compounds were subjected to a docking study using AutoDock 4.2. </P><P> Results: The active AQs have similar common structural characteristics. However, it is difficult to establish a structure-activity relationship as certain compounds are active despite the absence of the structural features exhibited by other active AQs. They have either ortho- or meta-arranged substituents and one free hydroxyl and/or carbonyl groups. When C-6 is substituted with a methyl group, the activity of AQs generally increased. 1,3-DihydroxyAQ (15) showed good antiplasmodial activity with an IC50 value of 1.08 &#181;M, and when C-6 was substituted with a methyl group, 1,3- dihydroxy-6-methylAQ (24) showed stronger antiplasmodial activity with an IC50 value of 0.02 &#181;M, with better selectivity index. Compounds 15 and 24 showed strong HRP2 activity and mild toxicity against hepatocyte cells. Molecular docking studies showed that the hydroxyl groups at the ortho (23) and meta (24) positions are able to form hydrogen bonds with heme, of 3.49 Å and 3.02 Å, respectively. </P><P> Conclusion: The activity of 1,3-dihydroxy-6-methylAQ (24) could be due to their inhibition against the free heme dimerization by inhibiting the HRP2 protein. It was further observed that the anthraquinone moiety of compound 24 bind in parallel to the heme ring through hydrophobic interactions, thus preventing crystallization of heme into hemozoin.

Malaria is a major public health problem caused by parasites, namely, Plasmodium vivax, P. falciparum, P. ovale and P. malariae transmitted via the bites of the female anopheles mosquito. The illness results in recurrent attacks of chills and fever and is characterized by high morbidity and mortality rates. G.macrophyllus is used traditionally to treat fever. On the basis of this, the extracts of G.macrophyllus are evaluated for its antimalarial activity with the β-hematin inhibition assay. During intra erythroctic growth and proliferation, hemoglobin is utilized as a major source of nutrition by the malaria parasite and haem (ferriprotoporphyrin IX) is released as a toxic byproduct. The major route of haem detoxification in the malaria parasite is through the formation of haemozoin or β-haematin. Thus, inhibition of the β-haematin is utilized as an antimalarial drug target. The ground dried roots of Goniothalamus macrophyllus were extracted in aqueous methanol and the crude extract was sequentially partitioned with n-hexane, chloroform and butanol. The crude methanol, hexane, chloroform, butanol and residual were assayed for ß-haematin inhibition. The inhibitory activity was determined by colorimetric method, measured at 405 nm with a microplate reader. Choloroquine, the most widely used antimalarial drug was used as the positive control. Based on the ß-haematin inhibiton assay, butanol extract exhibited an IC 50 value of 32 ± 0.06 µg/ml and was most potent towards the inhibition of β-hematin compared to the other extracts.