{
  "abstract": "A novel series of uracil–1,2,3-triazole hybrids was designed, synthesized, and evaluated as dual EGFR/CDK1 inhibitors to target cancer cell proliferation and survival. Synthesis was initiated via the nucleophilic substitution of 2-chloro-N-(1,3-dimethyl-2,6-dioxo-pyrimidin-4-yl)acetamide (3) with sodium azide, yielding the key intermediate 4. Subsequent copper-catalyzed azide–alkyne cycloadditions (CuAAC) with various terminal alkynes and 1,3-dicarbonyls afforded the target triazole analogues 6a,b, 8a–c, and 10b,c. In vitro antiproliferative screening against a panel of four human cancer cell lines (MCF-7, HT29, PANC1, A549) and one normal cell line (Vero) identified compound 10a as a potential candidate. Compound 10a exhibited potent dual inhibitory activity, with IC50 values of 0.082 µM and 0.131 µM for EGFR and CDK1, respectively; it was about 2.4-fold less potent than erlotinib against EGFR but about 4.8-fold more potent than roscovitine against CDK1. Mechanistically, 10a induced significant G0/G1-phase cell-cycle arrest (74.89% versus 60.04% in control) and increased apoptotic cells (early plus late apoptosis, 13.55% versus 1.16% in control) in HT29 cells, accompanied by upregulation of Caspase-3 and BAX, with a rise in Bcl-2 whose significance remains to be established. Molecular docking predicted that 10a can occupy the ATP-binding pockets of both EGFR and CDK1, and normal-mode analysis (iMODS) suggested that the docked complexes are structurally plausible. Computational ADMET profiling, however, flags several liabilities for 10a, including predicted hepatotoxicity, low predicted oral absorption and a short predicted half-life. These findings highlight the uracil–triazole scaffold, specifically compound 10a, as a promising starting point for the development of targeted dual EGFR/CDK1 anticancer therapeutics.",
  "abstract_shown": true,
  "affiliations": [
    "Chemistry Department, Faculty of Science, Minia University 61519 Minia Egypt",
    "Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University 61519 Minia Egypt",
    "Medicinal Chemistry Department, Faculty of Pharmacy, Minia National University New Minia 61768 Egypt",
    "Department of Chemistry and Chemical Engineering, Florida Institute of Technology Melbourne FL 32901 USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Asmaa H. Mohamed",
      "orcid": "0000-0003-3635-6968"
    },
    {
      "affs": [
        0
      ],
      "name": "Ashraf A. Aly",
      "orcid": "0000-0002-0314-3408"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Elshimaa M. N. Abdelhafez",
      "orcid": "0000-0002-0078-5261"
    },
    {
      "affs": [
        0
      ],
      "name": "Aya A. Fouly"
    },
    {
      "affs": [
        3
      ],
      "name": "Alan B. Brown",
      "orcid": "0000-0002-2669-5598"
    },
    {
      "affs": [
        0
      ],
      "name": "Sageda A. Gedamy",
      "orcid": "0009-0004-8910-9885"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ct0tf503xfncw.bib",
  "cited_by": 0,
  "doi": "10.1039/d6ra09088e",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13730394/?tool=EBI",
  "id": "ct0tf503xfncw",
  "issns": [
    "2046-2069"
  ],
  "landing_url": "https://europepmc.org/article/PMC/PMC13730394",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Chemistry"
    ],
    [
      "openalex",
      "1605|Synthesis and Characterization of Heterocyclic Compounds"
    ]
  ],
  "openalex": "W7225141141",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13730394/pdf/?tool=EBI",
  "pmcid": "PMC13730394",
  "pmid": "42979295",
  "published": "2026-11-03",
  "publisher": "Royal Society of Chemistry",
  "ris": "https://research.draconitic.com/paper/ct0tf503xfncw.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T15:20:45Z",
      "native_id": "PMC:PMC13730394",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13730394"
    },
    {
      "first_seen": "2026-11-07T12:22:57Z",
      "native_id": "PMC13730394",
      "source": "pmc",
      "url": "https://doi.org/10.1039/d6ra09088e"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "openalex:1605|Synthesis and Characterization of Heterocyclic Compounds",
      "subfield": "organic"
    }
  ],
  "title": "Design, click synthesis, and biological evaluation of novel uracil-1,2,3-triazole hybrids as dual EGFR/CDK1 inhibitors: antiproliferative activity, mechanistic insights, and in silico studies",
  "title_text": "Design, click synthesis, and biological evaluation of novel uracil-1,2,3-triazole hybrids as dual EGFR/CDK1 inhibitors: antiproliferative activity, mechanistic insights, and in silico studies",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T12:22:57Z",
  "url": "https://research.draconitic.com/paper/ct0tf503xfncw",
  "venue": "RSC advances",
  "versions": []
}