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Synthesis of novel α-aminophosphonate hybrids 8a–fwas accomplished by the reaction of 11-phenoxy-4-formylneocryptolepine 3, aminoalkylamino acridines 6a–fand diphenyl phosphite 7in the presence of lithium perchlorate as Lewis acid catalyst in methanol. The starting aldehyde 3was obtained by reaction of 11-chloroneocryptolpine 1with 4-hydroxybenzaldehyde 2in the presence of potassium carbonate in DMF, whereas 9-aminoalkylamino acridines 6a–fwere synthesized by reaction of 9-chloroacridine 4with appropriate diamines 5a–f. The structure of all synthesized hybrids was confirmed by spectroscopic methods and showed spectra in consistence with the expected structures. The antiproliferative activity of all synthesized hybrids was evaluated against HCT-116, MCF-7, HepG2 and A549 human cancer cell lines. The screened results proved that most of the reported compounds are potent, especially hybrid 8a, which displayed the highest activity against MCF-7, HepG2 and A549 cancer cell lines with IC508.2, 23.1 and 19.4 µM, respectively. This activity is significantly higher than the standard drug doxorubicin. Moreover, hybrid 8fshowed most potent activity against HCT-116 cancer cell line with IC502.4 µM higher than the reference drug doxorubicin (IC50:10.90 µM).