Abstract
BackgroundResistance of Plasmodium falciparum against common anti-malarial drugs emphasizes the need of alternative and more effective drugs. Synthetic derivatives of 1-(heteroaryl)-2-((5-nitroheteroaryl)methylene) hydrazine have showed in vitro anti-plasmodial activities. The present study aimed to evaluate the molecular binding and anti-plasmodial activity of synthetic compounds in vivo.MethodsThe molecular docking was used to study the binding of compounds to haem and Plasmodium falciparum lactate dehydrogenase (PfLDH). Acute toxicity of the synthetic compounds was evaluated based on the modified up & down method. The anti-plasmodial activity of the compounds was conducted by the two standard tests of Peters’ and of Rane, using chloroquine-sensitive Plasmodium berghei in mice. Also, the toxicity to the internal organs of mice was evaluated on the seventh day after the treatment in addition to the histopathology of their liver. Compound 3 that showed high activity in the lowest dose was selected for further pharmacodynamic studies.ResultsAccording to the docking studies, the active site of PfLDH had at least four common residues, including Ala98, Ile54, Gly29, and Tyr97 to bind the compounds with the affinity, ranging from − 8.0 to − 8.4 kcal/mol. The binding mode of ligands to haem revealed an effective binding affinity, ranging from − 5.1 to − 5.5 kcal/mol. Compound 2 showed the highest % suppression of parasitaemia (99.09%) at the dose of 125 mg/kg/day in Peters’ test. Compound 3, with 79.42% suppression, was the best in Rane’s test at the lowest dose (31 mg/kg/day). Compound 3 was confirmed by the pharmacodynamic study to have faster initial parasite elimination in the lowest concentration. The histopathology of the livers of mice did not reveal any focal necrosis of hepatocytes in the studied compounds.ConclusionsThe docking studies verified Pf LDH inhibition and the inhibitory effect on the haemozoin formation for the studied compounds. Accordingly, some compounds may provide new avenues for the development of anti-malarial drugs without liver toxicity, although further studies are required to optimize their anti-plasmodial activity.
Highlights
Resistance of Plasmodium falciparum against common anti-malarial drugs emphasizes the need of alternative and more effective drugs
In Africa, 213 million people were affected by malaria, which made it the most vulnerable continent in 2018 [1]
The materials and chemical reagents were purchased from Sigma-Aldrich Company (USA)
Summary
Resistance of Plasmodium falciparum against common anti-malarial drugs emphasizes the need of alternative and more effective drugs. Synthetic derivatives of 1-(heteroaryl)-2-((5-nitroheteroaryl)methylene) hydrazine have showed in vitro anti-plasmodial activities. The world malaria report 2019 estimated that there were 228 million cases of malaria in 2018 causing 405,000 global. With 272,000 deaths, children less than 5 were the most vulnerable group worldwide. Chloroquine (CQ) and artemisinin (ART) derivatives are the two main classes of antimalarial drugs [3]. Repetitive and inappropriate use of CQ caused drug resistance of malaria parasites. The epidemiological evidence predicts the “tsunami” of ART resistance in the world, called “super malaria”. In this situation, subsequent treatment failures with artemisinin-based combination therapy (ACT) have raised concerns about the loss of the only highly-effective treatment currently available to treat malaria [6]
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