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

• Published in: Bioorganic chemistry Vol. 121; p. 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: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.04.2022; Elsevier
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biochemistry & Molecular Biology; CDK2; Cell Line, Tumor; Cell Proliferation; Chemistry; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; EGFR; ErbB Receptors; Life Sciences & Biomedicine; Molecular Docking Simulation; Molecular Structure; Physical Sciences; Pyrimidine; Quinoline; Quinolines - pharmacology; Science & Technology; Structure-Activity Relationship; Synthesis; Topo; Quinoline; Synthesis; Topo; EGFR; CDK2; Pyrimidine; DRUG DISCOVERY; TOPOISOMERASE-I; CYCLIN-DEPENDENT KINASE; RING-SYSTEMS; ANTITUMOR; SOLUBILITY; INHIBITION; BIOLOGICAL EVALUATION; FUSED QUINOLINE-HETEROCYCLES; DERIVATIVES
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2022.105693

[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.