DESIGN, SYNTHESIS, ANTIMALARIAL EVALUATION AND COMPUTATIONAL STUDIES OF SOME CHALCONE DERIVATIVES

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Department of Pharmaceutical Sciences

ABSTRACT
Inspired by the previous findings on the structural requirements needed for good antimalarial activity by chalcones against Plasmodium proteases, seventeen chalcone derivatives were designed and synthesized using Claisen-Schmidt condensation of appropriate aldehydes and methyl ketones. The structures of these compounds were established using various spectroscopic techniques. Based on SciFinder search the compounds; P1, P2, P3, and P8 are new compounds not listed on any chemical data base. The synthesized chalcones were screened in mice against established P. berghii infection. Eleven compounds were active and P2 the most active compound exhibited significant percentage inhibition of 90.32% (p?0.05) at a dose of 100 mg/kg. An interesting observation was the demonstration of good antimalarial activity with the 3-quinolinyl A ring derivatives- P3, P4 and P8. The potential of the synthesized compounds to inhibit the synthesis of β-hematin was also evaluated but, only compounds P12 and P17 showed modest inhibition of β-hematin synthesis with percent inhibition of 59.28% and 49.04% respectively at a dose of 50 μg/kg. The prospects of dual inhibition of Plasmodium falciparum vital proteases; aspartic proteases (plasmepsin II and IV) and cysteine proteases (falcipain-2 and 3) of the seventeen chalcone derivatives was also investigated using in silico studies. Structure-based virtual screening using validated molecular docking revealed two potential hits (P3 and P4) with the best binding affinity and broad inhibition across all the proteases used. The crucial driving forces for receptor interaction and key interacting residues of the enzymes by the potential hits were established using molecular dynamics and binding free energy calculations. Simulation experiments revealed the stability of the docked ligands within all the enzymes. The ligands were found to interact with the residues at the active site and other sub-site regulating specificity for the falcipains system. With the plasmepsin systems, the ligands interact with the flap, covering the active site. From the different energetic contributions of the individual residues, it is evident that the binding process was principally favored by van der Waals and little affected by electrostatic energies while the polar solvation energy impaired it. With regard to the binding interactions, it appeared that the most contributing features of the ligands for receptor interactions are the quinoline ring, carbonyl group and 2- methoxy group. Therefore, the result from this work have identified quinolinyl chalcones with 2- methoxy substitution on ring B as potential candidates for further optimization as antimalarial against Plasmodium proteases.