Discovery of new pyrimido[5,4-c]quinolines as potential antiproliferative agents with multitarget actions: Rapid synthesis, docking, and ADME studies
2022; Elsevier BV; Volume: 121; Linguagem: Inglês
10.1016/j.bioorg.2022.105693
ISSN1090-2120
AutoresRamadan Ahmed Mekheimer, Samar M. R. Allam, Mariam A. Al‐Sheikh, Moustafa S. Moustafa, Saleh Mohammed Al‐Mousawi, Yaser A. Mostafa, Bahaa G. M. Youssif, Hesham A. M. Gomaa, Alaa M. Hayallah, Mohamed Abdel‐Aziz, Kamal Usef Sadek,
Tópico(s)Synthesis and biological activity
ResumoA 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.
Referência(s)