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. 2024 Jun 18:15:1192659.
doi: 10.3389/fphar.2024.1192659. eCollection 2024.

Antimalarial and antioxidant activities of novel artesunate-ellagic acid hybrid compound in vitro and in vivo

Ahmed A Ishola  1 , Joseph O Adebayo  1 , Isabela P Ceravolo  2 , Habibu Tijjani  3 , Edson S Bento  4 , Henrique F Goulart  5 , Alessandre C Crispim  4 , Elizabeth A Balogun  1 , Antonio E G Santana  5 , Antoniana U Krettli  2
Affiliations

Antimalarial and antioxidant activities of novel artesunate-ellagic acid hybrid compound in vitro and in vivo

Ahmed A Ishola et al. Front Pharmacol. .

Abstract

Introduction: Emergence of drug resistant strains of Plasmodium species has necessitated the search for novel antimalarials with unique mechanisms of action. Synthesis of hybrid compounds has been one approach to tackling this challenge. In this study, the synthesis of artesunate-ellagic acid hybrid compound (EA31) from ellagic acid and artesunate and its evaluation for antimalarial and antioxidant activities using in vitro and in vivo models were carried out. Method: EA31 was synthesized from artesunate and ellagic acid. The activities of the hybrid compound against Plasmodium falciparum W2 and P. berghei NK65 were evaluated, and its antioxidant activities were also determined. Results: The results revealed that EA31 was more active against P. falciparum W2 (chloroquine resistant) clone and less cytotoxic to buffalo green monkey kidney cell line compared to artesunate. EA31 was also active against Plasmodium berghei NK65 in vivo. The results revealed inhibition of β-hematin formation as one of the mechanisms of action of EA31. EA31 also exhibited antioxidant activities. Conclusion: The results revealed that EA31 may exert dual action of killing malaria parasite and mopping the reactive oxygen species that mediate the secondary complications of malaria.

Keywords: antimalarial; antioxidant; artesunate; ellagic acid; hybrid compound.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

SCHEME 1
SCHEME 1
Reaction scheme for the synthesis of the artesunate-ellagic acid hybrid molecule (EA31).
FIGURE 1
FIGURE 1
Artesunate-Ellagic acid hybrid compound.
FIGURE 2
FIGURE 2
In vitro antioxidant activity of ellagic acid-artesunate hybrid compound (A) DPPH radical scavenging activity (B) Nitric oxide radical scavenging activity (C) Ferric reducing antioxidant power (D) ABTS radical scavenging activity (E) Total antioxidant capacity. Values are Means ± SEM of four determinations. BHT, Butylated hydroxytoluene; EA00, Ellagic acid; EA31, Ellagic acid-Artesunate Hybrid Molecule. QUE, Quercetin; ABTS, 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic) acid; DPPH, 1,1-Diphenyl-2-picrylhydrazyl.
FIGURE 3
FIGURE 3
Effect of artesunate-ellagic acid hybrid on in vivo antioxidant parameters in the erythrocyte of Plasmodium berghei NK65-infected mice (A) malondialdehyde concentration (B) superoxide dismutase activity (C) catalase activity (D) glutathione peroxidase activity (E) glutathione reductase activity (F) reduced glutathione concentration. Values are means ± SEM of four determinations. Bars for each day with different alphabets are significantly different (p < 0.05).
FIGURE 4
FIGURE 4
Effect of artesunate-ellagic acid hybrid on in vivo antioxidant parameters in the liver of Plasmodium berghei NK65-infected mice (A) malondialdehyde concentration (B) superoxide dismutase activity (C) catalase activity (D) glutathione peroxidase activity (E) glutathione reductase activity (F) reduced glutathione concentration. Values are means ± SEM of four determinations. Bars for each day with different alphabets are significantly different (p < 0.05).
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