Heterocyclic Scaffold Modification of Chalcones: Piperidinyl and Morpholinyl Triazene Derivatives as Potent Blood...

The emergence of resistance to existing antimalarials, including artemisinin and its combinations, has intensified the need for new chemotypes with improved efficacy. In this study, a scaffold-hopping strategy was employed to design and develop two series of triazene-appended chalcones, piperidinyl (PiCs) and morpholinyl (MCs), by modifying our previously reported pyrrolidinyl chalcones (PCs). Both PiC and MC series exhibited moderate to good antimalarial activity, with several derivatives showing improved potency over the parent PCs against the Plasmodium falciparum 3D7 strain. Among them, MC-22 and MC-23 were the most active, exhibiting IC₅₀ values of 1.02 and 1.13 µg/mL, respectively, while PiC-5, PiC-22, and PiC-18 also demonstrated promising activity (IC₅₀ = 3.27 to 4.60 µg/mL). Structure-activity relationship analysis highlighted enhanced activity of ortho and meta-substituted derivatives, with the exception of para-CF₃ analogues. Molecular docking confirmed favourable interactions with Plasmodium falciparum-dihydrofolate reductase, and all the hit compounds were found to be non-hemolytic. These findings highlight the effectiveness of heterocyclic scaffold modification in enhancing antiplasmodial activity and demonstrate the potential of morpholine-based triazene-chalcones as promising antimalarial agents.