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Widespread resistance of  Plasmodium falciparum  to current artemisinin-based combination therapies necessitate the discovery of new medicines. Pharmacophoric hybridization has become an alternative for drug resistance that lowers the risk of drug–drug adverse interactions. In this study, we synthesized a new series of hybrids by covalently linking the scaffolds of pyrano[2,3-c]pyrazole with 4-aminoquinoline via an ethyl linker. All synthesized hybrid molecules were evaluated through in vitro screenings against chloroquine-resistant (K1) and -sensitive (3D7)  P. falciparum  strains, respectively. Data from in vitro assessments showed that hybrid  4b  displayed significant antiplasmodial activities against the 3D7 strain (EC 50  = 0.0130 ± 0.0002 μM) and the K1 strain (EC 50  = 0.02 ± 0.01 μM), with low cytotoxic effect against Vero mammalian cells. The high selectivity index value on the 3D7 strain (SI > 1000) and the K1 strain (SI > 800) and the low resistance index value from compound  4b  suggested that the pharmacological effects of this compound were due to selective inhibition on the 3D7 and K1 strains. Molecular docking analysis also showed that  4b  recorded the highest binding energy on  P. falciparum  lactate dehydrogenase. Thus,  P. falciparum  lactate dehydrogenase is considered a potential molecular target for the synthesized compound.

Synthesis, Molecular Docking, and Antimalarial Activity of Hybrid 4-Aminoquinoline-pyrano[2,3-c]pyrazole Derivatives