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

Abstract

Development and discovery of new antimalarial drugs are needed to overcome the multi-resistance of Plasmodium 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 via 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 Plasmodium knowlesi A1H1 and P. falciparum 3D7, as well as their molecular docking on Plasmodium falciparum dihydrofolate reductases-thymidylate synthase (PfDHFR-TS). Data from in vitro evaluation showed that chalcone Mannich-type base derivatives 2a, 2e, and 2h displayed potential antimalarial activities against P. knowlesi with EC₅₀ of 2.64, 2.98, and 0.10 μM, respectively, and P. falciparum 3D7 with EC₅₀ 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 in vitro assay of 2a, 2e, and 2h by displaying CDOCKER energy of -48.224, -43.292, and -45.851 kcal mol^-1. Therefore, the evidence obtained here supports that PfDHFR-TS is a putative molecular target for the synthesized compound.

Fig. 1. Chalcone derivatives possessed antimalarial properties.

Fig. 2. Reaction scheme of aminoalkylated chalcones derivatives 1(a–d) and 2(a–h) from substituted-benzaldehyde and substituted-acetophenone. (i) Kalium hydroxide (60%), ethanol, stir at room temperature (RT) overnight; (ii) aminoalkyl groups, formaldehyde, ethanol, stir for 20 hours. R, R1, R2 = functional group from aldehyde and ketone; R3 = aminoalkyl groups.

Fig. 3. Molecular structures of synthesized chalcones (1a–1d, yield in %) and aminoalkylated chalcones derivatives (2a–2h, yield in %).

Fig. 4. Visualization of the interaction (2-dimensional and 3-dimensional) among (a) chalcone derivative 2a, (b) chalcone derivative 2e, and (c) chalcone derivative 2h with PfDHFR-TS. The atom coloring scheme is as follows: carbons in grey, oxygen in red, and nitrogen in blue. Green lines represent hydrogen-bonding interactions, while the pink line represents π-bonding interactions.

Fig. 5. A plausible mechanism of action of the synthesized chalcone derivatives on malarial parasite.