Molecular Modeling, β-Hematin Interactions Evaluation Based on Antimalarial Compounds and Synthesis of Some Hydroxypyridinone Derivatives as New Scaffold |Biomedgrid

The principal mechanism in blood stage in malaria parasite is hematin crystallization which is the viable target of the antimalaria compounds. Molecular modeling, qualitative pharmacophore and docking evaluation of some reported and new derivatives such as acridinone were also performed to investigate binding interactions with the heme sheet. Moreover, a series of hydroxypyridinone analogues were designed and synthesized using the structure-based approach to develop new antimalaria compounds. A series has been synthesized and characterized by FT-IR, NMR spectroscopy and mass spectrometry. Our compounds with appropriate features were evaluated for β- hematin inhibitors compared to the chloroquine as an antimalarial compound. The structure-based model and biological activities have shown axial Fe-interactions and π-π stacking in synthesized compounds. The substitution of synthesized imines (5a-5c) and amines (6a-6c) compounds based on hydroxypyridinone evaluated with alteration lateral chains aromatic for inhibition of β-hematin formation according to the results of molecular docking. Hydrophobic and H-bond acceptor features of pharmacophore are essential to show the best biological activity that have helped to develop a pharmacophore model based on 2-ethylphenyl imino-substituted hydroxypyridinone. Also, these compounds were evaluated for their β-hematin inhibition activity.