Synthesis of Calix4resorcinarene Derivatives as Antimalarial Agents through Heme Polymerization Inhibition Assay

Malaria is an endemic disease in tropical countries, including Indonesia, with a high annual mortality rate. Because of that, serious attention shall be given to find new antimalarial agents that are highly active for medical treatment. In this work, we designed and synthesized three calix4resorcinarene derivatives and evaluated them as antimalarial agents through in vitro heme polymerization inhibitory assay. The calix4resorcinarenes were prepared from resorcinol and corresponding aldehyde derivatives in ethanol media through a cyclo-condensation reaction. The calix4resorcinarene products were obtained in 31.1–85.1% yield. The synthesized compounds were subjected to structure elucidation using spectroscopy techniques. The antimalarial activity of calix4resorcinarene with aromatic substituent (IC50 = 0.198 mg/mL) was higher than the aliphatic ones (IC50 = 0.282–0.814 mg/mL). It was found that all calix4resorcinarenes in this work exhibited stronger antimalarial activity than chloroquine diphosphate as the positive control (IC50 = 1.157 mg/mL). The calix4resorcinarenes could interact with hydrogen bonding, thus inhibiting the heme polymerization process. These findings demonstrate that calix4resorcinarene derivatives are potential antimalarial agents to be developed for effective medical treatment in the near future. © 2023, Gadjah Mada University. All rights reserved.