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

مؤلف البحث
Ramadan A. Mekheimer, Samar M. R. Allam, Mariam A. Al-Sheikh, Moustafa Sh. Moustafa, Saleh M. Al-Mousawi, Yaser A. Mostafa, Bahaa G. M. Youssif, Hesham A. M. Gomaa, Alaa M. Hayallah, Mohamed Abdelaziz, Kamal U. Sadek
تاريخ البحث
مجلة البحث
Bioorganic Chemistry
الناشر
Science direct
تصنيف البحث
Medicinal Chemistry
عدد البحث
121
سنة البحث
2022
صفحات البحث
105693
ملخص البحث

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