Rational Design of N‐2‐(7‐Chloroquinolin‐4‐ylamino)ethyl Amides Active Against Chloroquine‐Resistant Plasmodium falciparum

Abstract

ABSTRACT Motivated by the antimalarial potential demonstrated by benzamide derivatives of 4‐alkylamino‐7‐chloroquinolines against chloroquine‐resistant Plasmodium falciparum, we designed and synthesized a rational series of N‐2‐(7‐chloroquinolin‐4‐ylamino)ethyl amides to investigate the effects of electron‐withdrawing and donating substituents on antiplasmodial and cytotoxicity properties, from prediction to in vitro assays. From an initial screening of 22 chloroquine (CQ) analogs, 16 compounds with two distal amino groups in the alkyl linker showed IC50 values below 1000 nM against the CQ‐sensitive 3D7 strain. Next, their activity against the CQ‐resistant K1 strain, in silico toxicity, predicted using the pkCSM program, and in vitro cytotoxicity on HepG2 cells were evaluated. Benzamides containing electron‐withdrawing chlorine and nitro groups showed the most promising profiles, with IC50 values against the CQ‐resistant K1 strain (IC50 K1, 55–72 nM) and resistance index (RI, 0.7–1.9) values outperforming CQ (IC50 K1 = 141 nM, RI = 7.1). Although predicted to be hepatotoxic, these compounds were not cytotoxic to HepG2 cells at the tested concentrations, showing CC50 values above 12,500 nM and selectivity indices greater than 115. Compared with CQ, a 3D qualitative SAR model indicated that increased lipophilicity around the distal benzamide moiety enhances antiplasmodial activity against the K1 strain, contributing to the observed potency.