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In this work, a series of nineteen novel pyrano[2,3-c]pyrazole-4-aminoquinoline hybrids were synthesized as potent antimalarial agents by covalently linking the scaffolds of 4-aminoquinoline and pyrano[2,3-c]pyrazoles via an ethyl linker and characterized using Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy (NMR). Molecular docking was used to test each hybrid's and standard chloroquine's ability to bind to Plasmodium falciparum lactate dehydrogenase enzyme (PfLDH), an important enzyme in the parasite's glycolytic pathway. The hybrid compounds had a stronger binding affinity than the standard chloroquine (CQ). The schizontical antimalarial test of pyrano[2,3-c]pyrazole-4-aminoquinoline hybrid compound shows that all nineteen hybrid compounds were potent with the IC 50 values ranging from 0.0151 to 0.301 μM against the CQ-sensitive 3D7 P. falciparum strain, and were active against the CQ-resistant K1 P. falciparum strain with the IC 50 values ranging from 0.01895 to 2.746 μM. All the tested hybrid compounds were less potent than the standard drug chloroquine dipaspate (CQDP) against the CQ-sensitive 3D7 strain. In contrast, nine of the nineteen hybrids (16d, 16g, 16h, 16i, 16l, 16n, 16o, 16r, and 16s) displayed superior antimalarial activity than the CQDP against the CQ-resistant K1 P. falciparum strain. Among all the tested hybrids, 16c against the 3D7 strain and 16h against the K1 strain were the most promising antimalarial agents with 0.0151 and 0.01895 μM of IC 50 values, respectively. In addition, the compounds were selective, showing moderate to low cytotoxic activity against a human normal liver WRL68 cell line. The synthesis of pyrano[2,3-c]pyrazole-4-aminoquinoline hybrids introduces new chemical entities that have the potential to exhibit potent antimalarial activity. It could address the ongoing challenge of drug resistance in malaria treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)