Synthesis, in silico docking studies, and antiplasmodial activity of hybrid molecules bearing 7-substituted 4-aminoquinoline moiety and cinnamic acid derivatives

Abstract

This paper reports a series of nine hybrid compounds of 7-substituted 4-aminoquinoline and cinnamic acid as antiplasmodial agents. ¹ H NMR and ¹³ C NMR spectroscopic analysis and mass spectrometry studies were used to confirm the structures. The synthesized compounds were moderately active, with IC₅₀ values ranging from 1.8 to 16 µM against the Pf3D7 chloroquine-sensitive strain in vitro. Compound C11 was shown to be the most potent in this investigation, with an IC₅₀ value of 1.8 µM. Molecular docking studies revealed that compounds C14 and C17, with binding energies $\left(\Delta G^0\right)$ of -7.19 and -7.72 kcal/mol and inhibition constants (K_i ) of 5.36 and 2.20 µM, respectively, were the best inhibitor candidates. The results of the Frontier molecular orbitals revealed that compounds possessed a small HOMO-LUMO energy gap. The HOMO-LUMO energy distributions indicated that the cinnamic acid regions favored the LUMO distribution, while the quinoline regions favored the HOMO energy. The investigation of absorption, distribution, metabolism, excretion, and toxicity based on in silico ADME tools predicted that the compounds have a good drug-like character.

Keywords: plasmodium falciparum; 4-aminoquinoline; cinnamic acid; hybridization; malaria.