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 IC
50
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 IC
50
values against the CQ‐resistant K1 strain (IC
50
K1
, 55–72 nM) and resistance index (RI, 0.7–1.9) values outperforming CQ (IC
50
K1
= 141 nM, RI = 7.1). Although predicted to be hepatotoxic, these compounds were not cytotoxic to HepG2 cells at the tested concentrations, showing CC
50
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.