Plasmepsin II inhibitory potential of phytochemicals isolated from African antimalarial plants: a computational approach.

Plamepsin II has been identified as a therapeutic target in the Plasmodium falciparum's life cycle and may lead to a drastic reduction in deaths caused by malaria worldwide. Africa flora is rich in medicinal qualities and possesses both simple and complex bioactive phytochemicals. This study utilized computational approaches like molecular docking, molecular dynamics simulation, quantum chemical calculations and ADMET to evaluate the plasmepsin II inhibitory properties of phytochemicals isolated from African antimalarial plants. Molecular docking was carried out to estimate the binding affinity of 229 phytochemicals whereby ekeberin A, dichamanetin, 10-hydroxyusambaresine, chamuvaritin and diuvaretin were selected. Further, RMSD and RMSF plots from the 100 ns simulation results showed that the screened phytochemicals were stable in the enzyme's binding pocket. The quantum chemical calculation revealed that all the phytochemicals are strong electrophiles, while ekeberin A was identified as the most stable and dichamanetin as the most reactive. Also, ADMET studies established the drug candidacy of the phytochemicals. Thus, these phytochemicals could act as good antimalarial agents after extensive in vitro and in vivo studies.Communicated by Ramaswamy H. Sarma.

Comparative in vivo antimalarial activities of aqueous and methanol extracts of MAMA powder - A herbal antimalarial preparation.

ETHNOPHARMACOLOGICAL RELEVANCE: The choice of extraction solvent is a significant consideration in ethnomedicine as optimal extraction could influence the bioactivity of the herbal medicinal product. AIM OF STUDY: This study investigated the possible influence of the choice of solvents (methanol and water) for extracting MAMA Powder (MP) against Plasmodium berghei-infected mice to optimize its antimalarial activity and for developing other pharmaceutical dosage forms. MATERIALS AND METHODS: Aqueous and methanol extracts of MP, obtained through the decoction and soxhlet methods, respectively, were subjected to liquid chromatography-mass spectroscopy (LC-MS) for their respective fingerprints. The antimalarial activities of the methanol and aqueous extracts (12.5-100 mg/kg) were evaluated orally using the chemosuppressive test model on chloroquine-sensitive Plasmodium berghei-infected mice. The methanol extract was subjected to the established infection and prophylactic antimalarial tests with chloroquine (10 mg/kg) and pyrimethamine (1.25 mg/kg) as positive controls, respectively. The aqueous extract was investigated in chloroquine-resistant P. berghei using the chemosuppressive (12.5-800 mg/kg) and established infection (25-400 mg/kg) antimalarial models. RESULTS: The LC-MS fingerprints of both aqueous and methanol extracts revealed similar indole alkaloid contents. Chemosuppressive activity of the aqueous extract (75.3%) was significantly (p < 0.05) higher than the methanol extract (67.6%). In the chloroquine-resistant P. berghei infection experiments, the aqueous extract (400 mg/kg) exhibited significant parasite clearance (72%). CONCLUSION: The study concluded that the water extract with higher antimalarial activity could be optimized for chloroquine-resistant malaria and can thus facilitate the production of liquid and solid dosage forms.

Influence of MAMA decoction, an Herbal Antimalarial, on the Pharmacokinetics of Amodiaquine in Mice.

BACKGROUND AND OBJECTIVE: MAMA decoction (MD) is an antimalarial product prepared from the leaves of Mangifera indica L. (Anacardiaceae), Alstonia boonei De Wild (Apocynaceae), Morinda lucida Benth (Rubiaceae) and Azadirachta indica A. Juss (Meliaceae). A previous report showed that MD enhanced the efficacy of amodiaquine (AQ) in malaria-infected mice, thus suggesting a herb-drug interaction. The present study hence evaluated the effect of MD on the disposition of AQ in mice with a view to investigating a possible pharmacokinetic interaction. METHODS: In a 3-period study design, three groups of mice (n = 72) were administered oral doses of AQ (10 mg/kg/day) alone, concurrently with MD (120 mg/kg/day), and in the 3rd period, mice were given AQ after a 3-day pre-treatment with MD. Blood samples were collected between 0 and 96 h for quantification of AQ and its major metabolite, desethylamodiaquine, by a validated high-performance liquid chromatography method. RESULTS: Maximum concentrations of AQ increased by 12% with the concurrent dosing of MD and by 85% in the group of mice pre-treated with MD. The exposure and half-life of desethylamodiaquine increased by approximately 11% and 21%, respectively, with concurrent administration. Corresponding increases of approximately 20% and 33% of desethylamodiaquine were also observed in mice pre-treated with MD. CONCLUSION: MD influenced the pharmacokinetics of AQ and desethylamodiaquine, its major metabolite. The increase in the half-life and systemic exposure of AQ following its co-administration with MD may provide a basis for the enhanced pharmacological effect of the combination in an earlier study in Plasmodium-infected mice.

Evaluation of the combination of Uvaria chamae (P. Beauv.) and amodiaquine in murine malaria.

ETHNOPHARMACOLOGICAL RELEVANCE: The leaf and fruit of Uvaria chamae P. Beauv (Annonaceae) are used in antimalarial ethnomedical preparations. Therefore, they were investigated for antimalarial activities as well as possible herb-drug interaction with amodiaquine (AQ). MATERIALS AND METHODS: The methanol extracts of the leaf (UCL) and fruit (UCF) were administered orally at 100-800mg/kg/day in mice infected with chloroquine (CQ)-sensitive Plasmodium berghei NK65 using the four-day, curative and prophylactic antimalarial test models. The UCL was further evaluated at 100-800mg/kg as twice-daily doses and combinations of UCL+AQ using the four-day test. Mice infected with CQ-resistant P. berghei ANKA were treated with UCL at 400mg/kg and AQ at 10mg/kg - [UCL400+AQ10]mg/kg - in the four-day and curative test models. RESULT: At 800mg/kg/day, UCL, UCF gave chemosuppression of 42, 28% (four-day test), parasite clearance of 36.3, 49.5% on day 5 (curative test) and 64.3, 82.6% (prophylactic test), respectively. The twice-daily dose of UCL at 800mg/kg showed activity of 51.50% while the combination of [UCL200+AQ5]mg/kg exhibited chemosuppression of 91.66%, which was not significantly different (p>0.05) from AQ at 10mg/kg (85.41%). In the CQ-resistant P. berghei experiment, the combination gave a chemosuppression of 45.80%, significantly lower (p<0.05) than AQ (78.40%) while the parasite clearance was not significantly different from AQ (curative test). CONCLUSION: The leaf extract showed moderate chemosuppressive activity. The lower-dose combination of the leaf extract and amodiaquine had better antimalarial activity in CQ-sensitive murine malaria. However, the tested combination had no beneficial antimalarial effect in CQ-resistant murine malaria.

Evaluation of herbal antimalarial MAMA decoction-amodiaquine combination in murine malaria model.

CONTEXT: Co-administration of amodiaquine with MAMA decoction (MD), an herbal antimalarial drug comprising the leaves of Mangifera indica L. (Anacardiaceae), Alstonia boonei De Wild (Apocynaceae), Morinda lucida Benth (Rubiaceae) and Azadirachta indica A. Juss (Meliaceae) was investigated. The practice of concurrent administration of herbal medicines with orthodox drugs is currently on the increase globally. OBJECTIVE: The study was designed to investigate the possible enhancement of the antimalarial potency as well as possible herb-drug interaction resulting from concurrent administration of MAMA decoction with amodiaquine (AQ). MATERIALS AND METHODS: Combinations of MD with AQ were investigated in chloroquine (CQ)-sensitive Plasmodium berghei NK 65 in varying oral doses (mg/kg) at: sub-therapeutic [MD30 + AQ1.25], therapeutic [MD120 + AQ10] and median effective [MD40 + AQ3.8], using chemosuppressive and curative antimalarial test models. Secondly, P. berghei ANKA (CQ-resistant)-infected mice were orally treated with MD 120, 240, [MD120 + AQ10] and [MD240 + AQ10] mg/kg, using both models. The survival times of mice were monitored for 28 d. RESULTS: ED50 values of MD and AQ were 48.8 and 4.1 mg/kg, respectively. A total parasite clearance of CQ-sensitive P. berghei NK65 was obtained with the therapeutic combination dose in the curative test giving an enhanced survival time. In CQ-resistant P. berghei ANKA-infected mice, [MD120 + AQ10] and [MD240 + AQ10] mg/kg gave comparable activities with AQ (10 mg/kg) in both models. CONCLUSION: The therapeutic combination dose gave total parasite clearance of CQ-sensitive P. berghei NK65, whereas none of the doses tested showed notable activity against CQ-resistant P. berghei ANKA.

In vivo antimalarial evaluation of MAMA decoction on Plasmodium berghei in mice.

The use of decoctions of different plant materials is common practice in antimalarial ethnomedicine in Africa. Scientific evaluation of such herbal combinations to verify the claims is important. The study has evaluated the antimalarial efficacy of MAMA decoction (MD), a multicomponent herbal preparation and its individual plant components, namely leaves of Morinda lucida Benth [Rubiaceae] (ML), Azadirachta indica A. Juss [Meliaceae] (AI), Alstonia boonei De Wild [Apocynaceae] (AB) and Mangifera indica L [Anacardiaceae] (MI) in Plasmodium berghei-infected mice. Each decoction was prepared by boiling the powdered leaf in water, concentrated in vacuo and freeze-dried. The acute toxicity of MD (LD50=3.8 g/kg) was determined using Lorke's method. The antimalarial activities of MD and its plant components were evaluated by oral administration of the freeze-dried extracts (15-240 mg/kg) using the early malaria infection test model. The established malaria infection test was used to evaluate MD (60-240 mg/kg) while amodiaquine [10 mg/kg] (AQ) and distilled water were employed as the positive and negative controls, respectively. From the early malaria infection test, the effective doses at 50 % (ED50) and 90 % (ED90) for MD, AB, AI, ML, MI and AQ were 43, 79, 140, 134, 208 and 3.9 mg/kg and 202, 276, 291, 408, 480 and 9.2 mg/kg, respectively. For the established infection test, MD (240 mg/kg) and AQ gave parasite clearance of 55 and 95 % on day 5 of treatment. MD possesses antimalarial activity and is relatively safe.