Synthesis, in vitro antimalarial activity, cytotoxicity, and pharmacokinetic evaluation of chalcone-derived thiosemicarbazones

Abstract Six novel chalcone-derived thiosemicarbazones ( L1 - L6 ) were synthesised and characterised by FT-IR, DSC, elemental CHNS analysis, Q-TOF LC/MS, 1 H and 13 C NMR spectroscopy, with the structure of L3 further confirmed by single-crystal X-ray crystallography. In vitro evaluation against chloroquine-sensitive P. falciparum (3D7 strain) revealed potent antimalarial activity (IC 50 = 6.0–205.1 µM), with L4 exhibiting the highest potency (IC 50 = 6.0 µM). Cytotoxicity screening revealed that all compounds were non-toxic to human MRC-5 cells at a concentration of 200 µM. The predicted pharmacokinetic profiles revealed that the superior potency of L4 is underpinned by its high lipophilicity (LogP = 5.7) and low systemic clearance, which likely facilitates parasite penetration and sustained exposure. These results highlight L4 as a promising antimalarial lead compound worthy of further development.