Chalcone Mannich base derivatives: synthesis, antimalarial activities against Plasmodium knowlesi , and molecular docking analysis

Development and discovery of new antimalarial drugs are needed to overcome the multi-resistance of parasites to commercially available drugs. Modifying the substitutions on the amine groups has been shown to increase antimalarial activities and decrease cross-resistance with chloroquine. In this study, we have synthesized several chalcone derivatives the substitution of aminoalkyl groups into the aromatic chalcone ring using the Mannich-type reaction. The chalcone derivatives were evaluated for their antimalarial properties against A1H1 and 3D7, as well as their molecular docking on dihydrofolate reductases-thymidylate synthase (PfDHFR-TS). Data from evaluation showed that chalcone Mannich-type base derivatives 2a, 2e, and 2h displayed potential antimalarial activities against with EC of 2.64, 2.98, and 0.10 μM, respectively, and 3D7 with EC of 0.08, 2.69, and 0.15 μM, respectively. The synthesized compounds 2a, 2e, and 2h exerted high selectivity index (SI > 10) values on the A1H1 and 3D7 strains. The molecular docking analysis on PfDHFR-TS supported the assay of 2a, 2e, and 2h by displaying CDOCKER energy of -48.224, -43.292, and -45.851 kcal mol . Therefore, the evidence obtained here supports that PfDHFR-TS is a putative molecular target for the synthesized compound.