Synthesis, Activity Test and Molecular Docking of Novel Nitrophenylcalix[4]-2-methylresorcinarene Derivatives as Antimalarial Agent

Abstract

This research involved the synthesis, antimalarial assay and molecular docking of novel nitrophenylcalix[4]-2-methylresorcinarene derivatives. Calix[4]-2-methylresorcinarene derivatives, i.e., 2N, 3N and 4N, were synthesized in a one-step reaction through the cyclo-condensation reaction between resorcinol and aldehydes, i.e., 2-nitrobenzaldehyde, 3-nitrobenzaldehyde and 4-nitrobenzaldehyde, respectively. The reaction was carried out through the reflux method with ethanol and hydrochloric acid 37% as the solvent and catalyst, respectively. The synthetic products were characterized using FTIR, 1H-NMR, 13 C-NMR, and LC-MS spectrometers. Furthermore, the in vitro antimalarial assay was carried out against Plasmodium falciparum strain 3D7. The results showed that compounds 2N, 3N and 4N were successfully synthesized in 86.4, 78.6 and 95.7% yield, respectively. Compounds 2N, 3N and 4N showed active antimalarial activity with IC50 values of 2.35, 1.68 and 1.79 µM, respectively. The molecular docking studies revealed that nitrophenylcalix[4]-2-methylresorcinarenes gave the binding affinity in a range of-5.1 to-6.1 kcal/mol against the PfLDH receptor through the hydrogen bonds to Arg109, Thr101 and Lys102 amino acid residues. The molecular docking results agreed with the experimental antimalarial assay demonstrating the mechanism of action of nitrophenylcalix[4]-2-methylresorcinarenes as active antimalarial agents happened through the inhibition of the PfLDH receptor.