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The development of new anticancer drugs is still ongoing as a solution to the unsatisfactory results obtained by chemotherapy patients. Our previous studies on natural product-based anticancer agents led us to synthesize a new series of Plastoquinone (PQ) analogs and study their anticancer effects. Four members of PQ analogs (<b>PQ1</b>–<b>4</b>) were designed based on the scaffold hopping strategy; the design was later completed with structural modification. The obtained PQ analogs were synthesized and biologically evaluated against different cancer genotypes according to NCI-60 screening in vitro. According to the NCI results, bromo and iodo-substituted PQ analogs (<b>PQ2</b> and <b>PQ3</b>) showed remarkable anticancer activities with a wide-spectrum profile. Among the two selected analogs (<b>PQ2</b> and <b>PQ3</b>), <b>PQ2</b> showed promising anticancer activity, in particular against leukemia cell lines, at both single- and five-dose NCI screenings. This compound was also detected by MTT assay to reveal significant selectivity between Jurkat cells and PBMC (healthy) compared to imatinib. Further in silico studies indicated that <b>PQ2</b> was able to occupy the ATP-binding cleft of Abl TK, one of the main targets of leukemia, through key interactions similar to dasatinib and imatinib. <b>PQ2</b> is also bound to the minor groove of the double helix of DNA. Based on computational pharmacokinetic studies, <b>PQ2</b> possessed a remarkable drug-like profile, making it a potential anti-leukemia drug candidate for future studies.