Design, Synthesis and Dual-Stage Antimalarial Evaluation of β-Carboline−Metronidazole Hybrids: Structure−Activity Relationship and Molecular Docking Correlations

Malaria remains a major global health challenge, exacerbated by emerging drug-resistant Plasmodium strains. Herein, we report the design, synthesis, and dual-stage antimalarial evaluation of β-carboline−metronidazole hybrids. The synthesized hybrids, linked through ester and amide bonds, were evaluated in vitro against chloroquine-sensitive (Pf3D7) and resistant (PfK1) Plasmodium falciparum strains, as well as liver-stage Plasmodium berghei. Several compounds exhibited potent blood-stage inhibition (IC50 as low as 0.05 ± 0.02 μM), remarkable liver-stage activity surpassing primaquine, and favourable selectivity indices (>100). Notably, compound 8kkk achieved up to 95% suppression of parasitemia in P. berghei ANKA-infected Swiss mice at 50 mg/kg for four days. Pharmacokinetic studies revealed a distinct absorption and disposition profile. SAR analysis highlighted the importance of electronic nature and substitution pattern of the β-carboline scaffold, while molecular docking and fluorimetry analysis indicated strong binding to PfLDH. These findings suggest β-carboline−metronidazole hybrids as promising candidates for further development as dual-stage antimalarial agents.