Discovery of new pyrimido[5,4-c]quinolines as potential antiproliferative agents with multitarget actions: Rapid synthesis, docking, and ADME studies

[Display omitted] 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 th...

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Published in:Bioorganic chemistry 2022-04, Vol.121, p.105693-105693, Article 105693
Main Authors: Mekheimer, Ramadan A., Allam, Samar M.R., Al-Sheikh, Mariam A., Moustafa, Moustafa S., Al-Mousawi, Saleh M., Mostafa, Yaser A., Youssif, Bahaa G.M., Gomaa, Hesham A.M., Hayallah, Alaa M., Abdelaziz, Mohamed, Sadek, Kamal U.
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
CDK2
Cell Line, Tumor
Cell Proliferation
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
EGFR
ErbB Receptors
Molecular Docking Simulation
Molecular Structure
Pyrimidine
Quinoline
Quinolines - pharmacology
Structure-Activity Relationship
Synthesis
Topo
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Summary:[Display omitted] 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 compounds.
ISSN:0045-2068
1090-2120
DOI:10.1016/j.bioorg.2022.105693