Synthesis, In-vitro Antimalarial Activity and In silico Molecular Docking Study of Amino Chalcone Derivatives from 1-(2-aminophenyl)-3-(4- substituted-phenyl) prop-2-en-1-one and Dihydroquinolone Derivatives

Abstract

Background: Malaria is one of the major global health problems in developing countries and faced to the increased resistance of Plasmodium falciparum against existing malarial agents, it is important to look for new antimalarial compounds that will be active in multiple stage of Plasmodium falciparum's life cycle. Objective: The goal of this work was to synthesize Amino Chalcone derivatives and Dihydroquinolone derivatives, then evaluate their antimalarial activity by standard computational and biological methods. Methods: These amino chalcones were synthesized by the Claisen-Schmidt condensation and by intramolecular cyclization of substituted amino chalcones for the Dihydroquinolones derivatives. Their structures have been determined by NMR (1H and 13C). The in-vitro antimalarial assays were carried out by using the maturation test of trophozoites into schizonts. The molecular docking of these compounds was performed by AutoDock vina program using Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) (PDB ID 1J3I) as target protein. Results: All synthesized amino chalcones and dihydroquinolone derivatives were active against Fresh clinical isolates of Plasmodium falciparum with a range of EC50 ranging from 1.56 to 25µg/mL. However, the 2- phenyl-2, 3-dihydroquinolin-4-(1H)-one (DHQ 2) and 2- (4-methoxyphenyl)-2, 3-dihydroquinolin-4-(1H)-one (DHQ 4) showed excellent antimalarial activity with IC50 of 3.125 and 1.56 µg/mL, respectively. Whereas the IC50 of Chloroquine use as reference was 1.56µg/mL. Based on absorption, distribution, metabolism and excretion (ADME) properties, all synthetized compounds satisfied the Lipinski rule. Conclusion: The results suggest that these synthesized compounds (DHQ 2 and DHQ 4), could be used, after in vivo and clinical tests, like antimalarial supplement or even replace current drug therapies.