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

Abstract

Widespread resistance of <i>Plasmodium falciparum</i> 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) <i>P. falciparum</i> strains, respectively. Data from in vitro assessments showed that hybrid <b>4b</b> displayed significant antiplasmodial activities against the 3D7 strain (EC₅₀ = 0.0130 ± 0.0002 μM) and the K1 strain (EC₅₀ = 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 <b>4b</b> 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 <b>4b</b> recorded the highest binding energy on <i>P. falciparum</i> lactate dehydrogenase. Thus, <i>P. falciparum</i> lactate dehydrogenase is considered a potential molecular target for the synthesized compound.