Discovery of 5-Chlorobenzimidazole-based as Promising Inhibitors of Chloroquine-Resistant Plasmodium Strains: Synthesis, Biological Evaluation, Molecular Docking and Computational Studies
Jean Paul N’Guessan
Department of Therapeutic Chemistry, UFR Pharmaceutical Sciences, Félix Houphouët-Boigny University, 01 BP V 34 Abidjan, Côte d'Ivoire.
Songuigama Coulibaly
Department of Therapeutic Chemistry, UFR Pharmaceutical Sciences, Félix Houphouët-Boigny University, 01 BP V 34 Abidjan, Côte d'Ivoire.
Abdulrahim A. Alzain
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira, Sudan.
Drissa Sissouma
Laboratory of Structural Organic Chemistry, UFR SSMT, Félix Houphouët-Boigny University, 22 BP 582 Abidjan, Côte d'Ivoire.
William Yavo
Center for Research and Fight against Malaria, National Institute of Public Health of Côte d'Ivoire, 01 BP V 47 Abidjan, Côte d'Ivoire.
Mahama Ouattara *
Department of Therapeutic Chemistry, UFR Pharmaceutical Sciences, Félix Houphouët-Boigny University, 01 BP V 34 Abidjan, Côte d'Ivoire.
*Author to whom correspondence should be addressed.
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.
Keywords: Benzimidazole, Chalcone, Chemoresistance, Plasmodium falciparum, Docking, ADME properties