3-aryl-indolinones derivatives as antiplasmodial agents: synthesis, biological activity and computational analysis

Abstract

Malaria is an infectious illness, affecting vulnerable populations in Third World countries. Inspired by natural products, indole alkaloids have been used as a nucleus to design new antimalarial drugs. So, eighteen oxindole derivatives, <i>aza</i> analogues were obtained with moderate to excellent yields. Also, the saturated derivatives of oxindole and <i>aza</i> derivatives <i>via</i> H₂/Pd/C reduction were obtained in good yields, leading to racemic mixtures of each compound. Next, the inhibitory activity against <i>P. falciparum</i> of 18 compounds were tested, founding six compounds with IC₅₀ < 20 µM. The most active of these compounds was <b>8c</b>; however, their unsaturated derivative <b>7c</b> was inactive. Then, a structure-activity relationship analysis was done, founding that focused LUMO lobe on the specific molecular zone is related to inhibitory activity against <i>P. falciparum</i>. Finally, we found a potential inhibition of lactate dehydrogenase by oxindole derivatives, using molecular docking virtual screening.