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Curcumin, a pharmacological agent found in turmeric's rhizome, has been studied for its various therapeutic properties. However, its clinical development is hindered by its instability and low solubility in water, resulting in inadequate oral bioavailability. Two potential curcumin analogs, 2,5-bis(4'-hydroxy-3',5'-dimethoxybenylidene)cyclopentanone (PGV-5) and 2,6-bis(4'-hydroxy-3',5'-dimethoxybenylidene)cyclohexanone (HGV-5), are being developed to address this issue and enhance their therapeutic efficacy. The study aims to screen novel curcumin analog compounds by integrating in silico assessment of ADME properties, acute toxicity studies, and computational analysis. PGV-5 and HGV-5 are classified as Global Harmonized System of Classification and Labeling of Chemicals (GHS) class 4 and class 5, respectively, in acute toxicity assessment, as they cause histopathological changes in the heart and lungs. Their ADME profile indicates they serve as effective P-glycoprotein (P-gp) inhibitors, making them potential candidates for development as anti-multidrug resistance agents, particularly in cancer cells. Molecular docking on P-gp revealed significant inhibitory capability relative to curcumin, exhibiting comparable binding characteristics to the native ligand, as evidenced by superior docking scores. Subsequent molecular dynamics simulations confirmed the stable interaction of both compounds with P-gp, with HGV-5 showing the most favorable binding free energy. Target gene mapping revealed several pivotal targets including AKT1, STAT3, EGFR, and NF-κB1. These findings suggest that PGV-5 and HGV-5 merit further research as agents against multidrug-resistant in cancer, regardless of their toxicity profiles. Further confirmation of their effects requires more laboratory studies and clinical trials.