Potentials of Terpenoids as Inhibitors of Multiple Plasmodium falciparum Protein Drug Targets.

PURPOSE: The resistance of parasite to readily affordable antimalarial drugs, the high cost of currently potent drugs, and the resistance of vector mosquitoes to insecticides threaten the possibility of malaria eradication in malaria endemic areas. Due to the fact that quinine and artemisinin were isolated from plants sources, researchers have been encouraged to search for new antimalarials from medicinal plants. This is especially the case in Africa where a large percentage of the population depends on medicinal plant to treat malaria and other ailments. METHOD: In this study, we evaluated previously characterized Plasmodium-cidal compounds obtained from the African flora to identify their likely biochemical targets, for an insight into their possible antimalarial chemotherapy. Molecular docking study was first conducted, after which remarkable compounds were submitted for molecular dynamic (MD) simulations studies. RESULTS: From a total of 38 Plasmodium-cidal compounds docked with confirmed Plasmodium falciparum protein drug targets [plasmepsin II (PMII), histo-aspartic protein (HAP) and falcipain-2 (FP)], two pentacyclic triterpene, cucurbitacin B and 3 beta-O-acetyl oleanolic acid showed high binding affinity relative to artesunate. This implies their capacity to inhibit the three selected P. falciparum target proteins, and consequently, antimalarial potential. From the MD simulations studies and binding free energy outcomes, results confirmed that the two compounds are stable in complex with the selected antimalarial targets; they also showed excellent binding affinities during the 100 ns simulation. CONCLUSION: These results showed that cucurbitacin B and 3 beta-O-acetyl oleanolic acid are potent antimalarials and should be considered for further studies.

Antioxidant defense system induced by cysteine-stabilized peptide fraction of aqueous extract of Morinda lucida leaf in selected tissues of Plasmodium berghei-infected mice.

OBJECTIVE: This study evaluated the responses of some antioxidant parameters in selected tissues of Plasmodium berghei-infected mice treated with cysteine-stabilized peptide fraction (CSPF) of aqueous extract of Morinda lucida leaf. METHODS: Fifty-six mice were randomly divided into seven groups. Group A (normal control) was uninfected and received 5% dimethyl sulfoxide (DMSO). Mice in Groups B (negative control), C, D, E and F were inoculated with P. berghei NK65 and were administered with 5% DMSO and 15.63, 31.25, 61.5 and 125 mg/kg body weight of CSPF respectively. Group G animals, were also inoculated with P. berghei NK65, and received 20 mg/kg body weight of chloroquine. The administration lasted for three days, after which malondialdehyde (MDA) concentration and various antioxidant parameters in selected tissues of mice were determined on days 4 and 8 post-inoculation. RESULTS: The results revealed that MDA concentration was significantly increased (P < 0.05) in the tissues of the negative control and chloroquine-treated groups. The increased MDA concentration was reduced by CSPF in a dose-dependent manner, which was significant (P < 0.05) at higher doses. The activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase and the concentration of reduced glutathione were significantly reduced (P < 0.05) in the tissues of the negative control animals compared to the normal controls. This observed reduction in the negative control animals was reverted in a dose-dependent manner in infected animals given CSPF, even to the range of the normal controls at highest dose, as did chloroquine. CONCLUSION: The results suggest that CSPF of M. lucida leaf extract may induce the antioxidant defense system in vivo against Plasmodium species infection.

Cysteine-stabilised peptide extract of Morinda lucida (Benth) leaf exhibits antimalarial activity and augments antioxidant defense system in P. berghei-infected mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Cysteine-stabilised peptides (CSP) are majorly explored for their bioactivities with applications in medicine and agriculture. Morinda lucida leaf is used indigenously for the treatment of malaria; it also contains CSP but the role of CSP in the antimalarial activity of the leaf has not been evaluated. AIM OF THE STUDY: This study was therefore performed to evaluate the antimalarial activity of partially purified cysteine-stabilised peptide extract (PPCPE) of Morinda lucida leaf and its possible augmentation of the antioxidant systems of liver and erythrocytes in murine malaria. MATERIALS AND METHODS: PPCPE was prepared from Morinda lucida leaf. The activity of PPCPE was evaluated in vitro against Plasmodium falciparum W2 and its cytotoxicity against a BGM kidney cell line. PPCPE was also evaluated for its antimalarial activity and its effects on selected liver and erythrocyte antioxidant parameters in P. berghei NK65-infected mice. RESULTS: PPCPE was not active against P. falciparum W2 (IC50: >50µg/ml) neither was it cytotoxic (MLD50: >1000µg/ml). However, PPCPE was active against P. berghei NK65 in vivo, causing 51.52% reduction in parasitaemia at 31.25mg/Kg body weight on day 4 post-inoculation. PPCPE significantly reduced (P < 0.05) malondialdehyde concentrations in the liver and erythrocyte at higher doses compared to untreated controls. PPCPE increased glutathione concentration and activities of glutathione peroxidase, glutathione reductase, superoxide dismutase and catalase in a dose-dependent manner, which was significant (P < 0.05) at higher doses compared to the untreated controls. CONCLUSION: The results suggest that PPCPE may require bioactivation in vivo in order to exert its antimalarial effect and that PPCPE may augment the antioxidant defense system to alleviate the reactive oxygen species-mediated complications of malaria.