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In our efforts to design mono‐carbonyl analogues of curcumin with potential antiplasmodial activity, diarylidenecyclopentanone (DACP) derivatives, Ia–Iu and II–V, have been synthesized and characterized using 1H NMR, 13C NMR, IR, UV–Vis, and mass spectrometry. Structure of one of these DACPs has been verified by single crystal XRD. At the outset, all 25 DACPs were first screened at 12.5 µM for their in vitro antiplasmodial activity against the chloroquine (CQ)‐sensitive Pf3D7. The three most potent compounds (In, It, and Ik) were further tested at <10 µM concentrations against Pf3D7, PfINDO (CQ resistant), and PfMRA‐1240 (Artemisinin resistant) strains for determination of their IC50s and resistance indices. The drug profile of the DACPs was found to be very promising, with the most active compound It (IC50 1.39 µM against PfINDO) showing a selectivity index of ∼17 tested using HUH‐7 and HEK‐293T mammalian cell lines. Molecular docking studies with Pf pyridoxal synthase showed a good correlation between docking scores of DACPs and in vitro antiplasmodial activity. Further, high conformity with Lipinski's parameters indicates that these DACPs are promising antiplasmodial lead compounds. [ABSTRACT FROM AUTHOR]