N ¹-{4-[(10S)-Dihydroartemisinin-10-oxyl]}phenylmethylene-N ²-(2-methylquinoline-4-yl)hydrazine derivatives as antiplasmodial falcipain-2 inhibitors

A series of N ¹-{4-[(10S)-dihydroartemisinin- 10-oxyl]}phenylmethylene-N ²-(2-methylquinoline-4-yl) hydrazine derivatives 9a-9n possessing 4-quinolylhydrazone and artemisinin cores were herein synthesized and evaluated for their activities against cysteine protease falcipain- 2 of Plasmodium falciparum. The structures were clearly confirmed by elemental analysis, ¹H NMR, and mass spectra. The pharmacological results indicated that all compounds showed excellent activity against recombinant falcipain-2 (IC ₅₀ = 0.15-2.28 μM). The best one of this series was compound 9d (IC ₅₀ = 0.15 μM). The molecular docking results showed that the compound 9d made close contact with the key active site of cysteine protease falcipain-2.