Artesunate-Procyanidin Hybrid Compound: Synthesis, In vitro and In vivo Antimalarial, Antioxidant and Toxicological Effects

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The goal of global eradication of malaria has remained elusive due to the rapid spread of drug resistant parasites, necessitating urgent development of novel antimalarials. Therefore, the aim of this study was to synthesize a hybrid compound of artesunate and procyanidin and evaluate its antimalarial, antioxidant and toxicological effects using various models. The objectives were to: (i) synthesize and chracterise a hybrid compound from artesunate and procyanidin; (ii) evaluate the in vitro antiplasmodial activity and cytotoxicity of the compound; (iii) evaluate its mechanisms of action; (iv) evaluate its suppressive and curative antimalarial activities in Plasmodium berghei NK65-infected mice; (v) evaluate the protein-ligand interactions; (vi) evaluate the in vitro and in vivo antioxidant activities of the compound; and (viii) evaluate its toxic effects. Artesunate-procyanidin hybrid compound was synthesized using standard chemical protocols and the structure was elucidated using Nuclear Magnetic Resonance and Infra-Red spectroscopy. The compound was evaluated for its activity against Plasmodium falciparum W2 strain in vitro and P. berghei NK65 in vivo. Inhibition of β-hematin formation, red blood cell lysis and cytotoxicity against Buffalo Green Monkey (BGM) kidney cell line of the compound were evaluated. The compound was evaluated for antioxidant activity using in vitro and in vivo models and for toxic effects using selected organ function indices of mice. Protein-ligand interactions were evaluated using molecular docking. Data were analyzed using Analysis of Variance at P<0.05. The findings of this study were that the hybrid compound: i. was synthesized as a brownish crystal with two pharmacopores linked together by ester bond; ii. was active against P. falciparum W2 (IC50: 0.0335 µg/ml), though its activity was lower than that of artesunate, but higher than that of procyanidin and it was less toxic to BGM cell line (MLD50: 155 µg/ml); iii. caused higher inhibition of β-haematin formation in vitro (IC50: 42.46 µg/ml) compared to chloroquine (IC50: 55.53 µg/ml), though was lower than that of artesunate (IC50: 17.79 µg/ml) and did not cause red blood cell membrane perturbation; iv. exhibited higher suppressive activity (ED50: <5 mg/kg) than artesunate on day 4 post-inoculation and curative activity (ED50: <5 mg/kg) which favourably compared with artesunate on day 6 post-inoculation against P. berghei NK65 in mice; v. exhibited higher binding affinity for P. falciparum Lactate Dehydrogenase (-9.6 kcal/mol) compared to artesunate (-6.2 kcal/mol) and procyanidin (-8.0 kcal/mol); vi. exhibited higher ferric ion reducing power and DPPH scavenging activity (IC50: 19.68 µg/ml) compared to butylated hydroxytoluene in vitro and caused significant increase (P< 0.05) in glutathione peroxidase, and glutathione-S-transferase activities in RBC,heart, liver, kidney, and brain of P. berghei-infected mice compared to untreated infected controls; and vii. had no significant effect (P>0.05) on atherogenic index and plasma concentrations of sodium, calcium, creatinine, urea and bilirubin but significantly reduced (P< 0.05) brain Na+,K+Adenosine triphosphatase activity in mice at all doses administered compared to controls. The study concluded that hybrid compound exhibited antimalarial activity (which favourably compared with artesunate) and antioxidant activity in vivo. Artesunate-procyanidin hybrid compound may be explored as an alternative therapy for malaria.



Artesunate, Procyanidin, Hybrid Compound, Synthesis, In vitro, In vivo, Antimalarial, Antioxidant, Toxicological Effects