Despite emergence of resistance to CQ and other 4-aminoquinoline drugs in most of the endemic regions, research findings provide considerable support that there is still significant potential to discover new affordable, safe, and efficacious 4-aminoquinoline antimalarials. In present study, new side chain modified 4-aminoquinoline derivatives and quinoline-acridine hybrids were synthesized and evaluated in vitro against NF 54 strain of Plasmodium falciparum. Among the evaluated compounds, compound 17 (MIC=0.125 μg/mL) was equipotent to standard drug CQ (MIC=0.125 μg/mL) and compound 21 (MIC=0.031 μg/mL) was four times more potent than CQ. Compound 17 showed the curative response to all the treated swiss mice infected with CQ-resistant N-67 strain of Plasmodium yoelii at the doses 50 mg/kg and 25 mg/kg for four days by intraperitoneal route and was found to be orally active at the dose of 100 mg/kg for four days. The promising antimalarial potency of compound 17 highlights the significance of exploring the privileged 4-aminoquinoline class for new antimalarials.