{
  "abstract": "A series of twelve novel dihydropyrimidine (DHPM)-amide hybrid conjugates (6a-c, 8a-c, 10a-c, and 12a-c) were rationally designed, synthesized, and biologically evaluated as potential EGFR-targeted anticancer agents against A549 non-small cell lung carcinoma (NSCLC) cells. The target compounds were constructed via a convergent two-step protocol: Biginelli multicomponent condensation to assemble the DHPM-carboxylic acid core (4a-c), followed by EDC·HCl/HOBt-mediated chemoselective amide coupling with four clinically inspired amine fragments derived from erlotinib/gefitinib (series 10), cabozantinib (series 8), imatinib (series 12), and a sorafenib bioisostere (series 6). All compounds were characterized by IR, ¹H NMR, ¹³C NMR, and low-resolution ESI-MS. MTT cytotoxicity screening identified compound 10b as the most potent analogue (IC₅₀ = 16.11 ± 0.11 µg mL⁻¹, equivalent to 23.31 µM), exceeding the molar potency of the reference methotrexate (IC₅₀ = 15.00 ± 0.48 µg mL⁻¹, equivalent to 33.01 µM). It should be noted that methotrexate is a dihydrofolate reductase inhibitor included solely as a general cytotoxicity control and is not a mechanistically matched EGFR comparator; the comparison therefore reflects relative cytotoxic potency only and does not imply EGFR selectivity. Molecular docking against EGFR (PDB 1M17), an erlotinib-bound inactive-conformation structure, returned the most favourable score for 10b (score = -7.819 kcal mol⁻¹), with predicted hydrogen bonds to ASP831 and LYS721, a halogen contact at ILE765, and an extensive 15-residue hydrophobic network; these poses indicate compatibility with the erlotinib-binding pocket rather than a confirmed ATP-competitive binding mode. DFT calculations at B3LYP/6-311G(d,p) characterised the electronic structure of the isolated molecule (ΔE = 4.045 eV; ω = 3.155 eV) and are reported as a physicochemical description only, without implying a causal link to cellular activity. Normal mode analysis indicated conformational stability of the 10b-EGFR complex, collectively identifying 10b as a promising lead for further optimisation and mechanistic evaluation, for which direct EGFR kinase assays remain necessary.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemistry, Atamiya University Rajkot 360005 Gujarat India Suresh.koradiya@gmail.com.",
    "Department of Chemistry, Shri M. P. Pandya Science College, Shri Govind Guru University Lunawada-389230 Godhra Gujarat India dryobhola@gmail.com."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Sagar P Kothadiya"
    },
    {
      "affs": [
        1
      ],
      "name": "Jay B Maheta"
    },
    {
      "affs": [
        1
      ],
      "name": "Darshna K Lakhnotra"
    },
    {
      "affs": [
        1
      ],
      "name": "Yogesh O Bhola",
      "orcid": "0000-0002-8882-5714"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Sureshkumar B Koradiya"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5s1zxttrfrpp8.bib",
  "cited_by": 0,
  "doi": "10.1039/d6ra08838d",
  "fulltext_url": "https://europepmc.org/articles/PMC13678441",
  "id": "5s1zxttrfrpp8",
  "issns": [
    "2046-2069"
  ],
  "landing_url": "https://europepmc.org/article/MED/42898914",
  "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": [
    [
      "openalex",
      "1605|Multicomponent Synthesis of Heterocycles"
    ]
  ],
  "openalex": "W7222958113",
  "pdf_url": "https://europepmc.org/articles/PMC13678441?pdf=render",
  "pmcid": "PMC13678441",
  "pmid": "42898914",
  "published": "2026-10-19",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/5s1zxttrfrpp8.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:33Z",
      "native_id": "MED:42898914",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42898914"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "openalex:1605|Multicomponent Synthesis of Heterocycles",
      "subfield": "organic"
    }
  ],
  "title": "Design, synthesis, and anticancer evaluation of Biginelli-derived DHPM-amide hybrids bearing clinically inspired kinase-directed pharmacophores: EGFR docking and DFT studies.",
  "title_text": "Design, synthesis, and anticancer evaluation of Biginelli-derived DHPM-amide hybrids bearing clinically inspired kinase-directed pharmacophores: EGFR docking and DFT studies.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:33Z",
  "url": "https://research.draconitic.com/paper/5s1zxttrfrpp8",
  "venue": "RSC advances",
  "versions": []
}