Abstract
Background: To overcome drug resistance to current antimalarial drugs, we propose the synthesis and in vitro evaluation of the antiplasmodial activity of a series of 5-chlorobenzimidazolyl-chalcones against chloroquino sensitive (CQ-S) and chloroquino resistant (CQ-R) strains of P. falciparum.
 Objective: This study aimed to establish through structure-activity relationship studies and docking, the structural elements essential for antiplasmodial activities.
 Methods: The antiplasmodial activity of these benzimidazolylchalcones was carried out according to the Rieckmann microtest technique, followed by the determination of the concentrations inhibiting 50% of the production of parasitic HRP2 antigens (IC50) by ELISA. Chloroquine was used as a reference molecule with a sensitivity threshold set at 100 µM. Molecular docking was performed using sensitive (PDB ID: 1J3I) and resistant (PDB ID: 4DP3) dihydrofolate reductase-thymidylate synthase proteins (PfDHFR-TS).
 Results: All benzimidazolylchalcones tested expressed antiplasmodial activities especially against chloroquine resistant isolates (IC50 = 0.32-44.38 µM). The best profile against both isolates was the methoxylated derivative (3e) with an IC50 ranging from 0.32 to 1.96 µM. This compound had the best antimalarial activity against CQ-S isolates. On CQ-R isolates, the unsubstituted 5-chlorobenzimidazole derivative (3b) had exalted activity (IC50 = 0.78 µM). We selected a weakly active non-chlorinated derivative 3a and chlorinated derivatives 3b, 3d, 3e and 3f) with IC50< 3µM against the chloroquine-resistant strain to perform docking studies. These revealed that the pyrrolic nitrogen of benzimidazole and the ketone of propenone are the main chemical entities involved in the interaction at the receptor. Moreover, ADMET studies showed favorable pharmacokinetic properties.
 Conclusion: Molecular docking studies confirmed the experimental findings and revealed the possible interactions pattern. Derivatives 3b and 3e, which showed promising binding affinities against PfDHFR-TS, can be proposed as lead compounds for the development of antimalarial drug candidates.
Highlights
Malaria is a parasitic infection transmitted to people through the bites of infected mosquitoes due to species of the genus Plasmodium whose main infectious agent, Plasmodium falciparum, is formidable [1]
This modulation contributes to the exaltation of antiplasmodial activities on both chloroquinesensitive (IC50 = 10.65 μM) and chloroquineresistant (IC50 = 0.78 μM) P. falciparum isolates by 4 to 9 times compared to its non-chlorinated analogue 3a
The present study was carried out with the aim of extending the evaluation of the antiplasmodial activities of benzimidazolyl-chalcones initiated in a previous study and which highlighted the excellent potentiality of the 5-chlorinated derivative
Summary
Malaria is a parasitic infection transmitted to people through the bites of infected mosquitoes due to species of the genus Plasmodium whose main infectious agent, Plasmodium falciparum, is formidable [1]. Estimates point to 229 million malaria episodes in 2019, of which 94% (215 M) were in the WHO African Region In this region, the number of deaths due to malaria has decreased from 620,000 to 409,000 over the period 2009-2019 representing a reduction in malaria cases and death rates of 18% and 34% since 2010 [5]. The number of deaths due to malaria has decreased from 620,000 to 409,000 over the period 2009-2019 representing a reduction in malaria cases and death rates of 18% and 34% since 2010 [5] These figures are all the more alarming as we are witnessing an increase in morbidity caused by resurgence of P. falciparum chemoresistance to almost all available antimalarial drugs, including artemisinin derivatives, the most potent and safe antimalarial drugs [6]. Objective: This study aimed to establish through structure-activity relationship studies and docking, the structural elements essential for antiplasmodial activities.
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