European Journal of Biomedical and Pharmaceutical Sciences

IN-VITRO AND IN-SILICO EVALUATION OF A NOVEL INDENOIMIDAZOLE DERIVATIVE IN A MOUSE MODEL

Ehigie Leonard O, Olaniyan Lamidi W. B.*, Olatomide Fadare, Ehigie Adeola F, Alabi Olubunmi T, Ojeniyi Fiyinfoluwa D and Onikepo Adesina A

ABSTRACT

Malaria remains a major public health issue in tropical and subtropical regions, exacerbated by the rapid emergence of drug-resistant Plasmodium species. This study aimed to develop a novel antimalarial agent by investigating a synthesized indenoimidazole derivative as a potential transketolase inhibitor, a key enzyme in the pentose phosphate pathway. The research sought to provide a new avenue for antimalarial therapy. (E)-3a,8a-dihydroxy-3-((2,4-hydroxybenzylidene)amino)-2-thioxo-1,3,3a,8a-tetrahydroindeno[1,2-d] imidazol-8(2H)-one, was synthesized and characterized using IR and NMR spectroscopy. Molecular docking (AutoDock Vina) and molecular dynamics (MD) simulations (GROMACS) assessed the compound's binding affinity and stability with Plasmodium transketolase. In-vivo studies evaluated antimalarial efficacy using Plasmodium berghei-infected mice, with chemosuppression assays and survival index measurements conducted at doses of 5, 10, and 25 mg/kg. Results indicated absorption band in IR (3344.71 cm⁻¹) and chemical shifts in ¹H NMR confirming the compound’s structure. Docking studies showed a binding affinity of -7.8 kcal/mol compared to -6.7 kcal/mol for thiamine pyrophosphate. MD simulations revealed a stable protein-ligand complex with RMSD ~0.2 nm over 50 ns. In-vivo tests showed 85.12% chemosuppression and 100% survival index at 25 mg/kg, outperforming chloroquine (66.58% chemosuppression, 68.97% survival). In conclusion, the indenoimidazole derivative demonstrated strong binding affinity, stability, and significant in-vivo antimalarial activity, suggesting its potential as a transketolase inhibitor. Future research should focus on pharmacokinetics optimization and clinical trials to confirm its efficacy and safety.

Keywords: Indenoimidazole derivative, antimalarial activity, transketolase inhibitor, molecular docking, chemosuppression, Plasmodium berghei.