Synthesis and in vitro/in silico evaluation of the antimalarial activity of potential amino-quinoline derivatives

Abstract

In this study, a series of N-arylamino-7-chloroquinolines were synthesized via an alkylation reaction involving aniline derivatives (2) and 4,7-dichloroquinoline (1). Additionally, the synthesis of a library of N-aryl-N-benzylamino-7-chloroquinoline analogues, modified on the aniline nitrogen, has also reported. A structure-activity relationship (SAR) study was conducted to evaluate the biological efficacy and safety of these derivatives against chloroquine-sensitive (Pf3D7) and chloroquine-resistant (PfW2) Plasmodium falciparum strains. Compounds 5i and 5c showed promising efficacy against the Pf3D7 strain with IC₅₀ values of 0.25 μM and 0.54 μM, respectively, while compound 5l demonstrated significant activity against the PfW2 strain with an IC₅₀ of 5.82 μM. The cytotoxicity of these compounds was also evaluated on HUVEC cell lines. Additionally, their pharmacological and pharmacokinetic (ADME) properties were studied to predict their fate and identify promising candidates for further clinical studies.