A novel series of pyrimido[5,4-c]quinoline derivatives variously substituted at positions 2 and 5 have been
synthesized, in good to excellent yields, via rapid base-catalyzed cyclization reaction of 2,4-dichloroquinoline-3-
carbonitrile (5) with guanidine hydrochlorides 6a-c. All the synthesized compounds were screened for their in
vitro antiproliferative activity. The most active hybrids 26a-d, 28a-d, and 30B were assessed against topoisomerase
(topo) I, topo IIα, CDK2, and EGFR. The majority of the tested compounds exhibited selective topo I
inhibitory activity while had weak topo IIα inhibitory action with compounds 30B and 28d, showed better topo I
inhibitory activity than the reference camptothecin. Compound 30B, the most potent derivative as antiproliferative
agent, exhibited moderate activity against CDK2 (IC50 = 1.60 μM). The results of this assay show
that CDK2 is not a potential target for these compounds, implying that the observed cytotoxicity of these
compounds is due to a different mechanism. Compounds 30B, 28d, and 28c were found to be the most potent
against EGFR and their EGFR inhibitory activities (IC50 = 0.40 ± 0.2, 0.49 ± 0.2, and 0.64 ± 0.3, respectively)
relative to the positive control erlotinib (IC50 = 0.07 ± 0.03 μM). These results revealed that topo I and EGFR are
attractive targets for this class of chemical compound