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

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

  • Bioorg Chem. 2022 Apr;121:105693. doi: 10.1016/j.bioorg.2022.105693.
Ramadan A Mekheimer 1,  Samar M R Allam 2,  Mariam A Al-Sheikh 3,  Moustafa S Moustafa 4,  Saleh M Al-Mousawi 5,  Yaser A Mostafa 6,  Bahaa G M Youssif 7,  Hesham A M Gomaa 8,  Alaa M Hayallah 9,  Mohamed Abdelaziz 10,  Kamal U Sadek 2
Affiliations

Affiliations

  • 1 Department of Chemistry, Faculty of Science, Minia University, Minia 61519, Egypt. Electronic address: rmekh@yahoo.com.
  • 2 Department of Chemistry, Faculty of Science, Minia University, Minia 61519, Egypt.
  • 3 Department of Chemistry, Jeddah University, Faculty of Sciences-Al Faisaliah, Jeddah 21493, Saudi Arabia.
  • 4 Department of Chemistry, Faculty of Science, Kuwait University, P.O. Box 12613, Safat 13060, Kuwait.
  • 5 Department of Chemistry, Faculty of Science, Kuwait University, P.O. Box 12613, Safat 13060, Kuwait. Electronic address: salehalmousawi@hotmail.com.
  • 6 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
  • 7 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt. Electronic address: bahaa.youssif@pharm.aun.edu.eg.
  • 8 Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf 2014, Saudi Arabia.
  • 9 Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sphinx University, New Assiut, Egypt.
  • 10 Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt.
PMID: 35219045 DOI: 10.1016/j.bioorg.2022.105693
Abstract

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.

Keywords

CDK2; EGFR; Pyrimidine; Quinoline; Synthesis; Topo.

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