{
  "abstract": "Erectile dysfunction (ED) remains a global health burden, yet the clinical utility of tadalafil is constrained by its poor aqueous solubility, cross-inhibition of homologous PDE isoforms, and an efficacy ceiling that cannot be overcome by dose adjustment alone. Herein, a series of diketopiperazine-based tadalafil analogues were designed and synthesized by decorating the amide nitrogen with flexible carbon chains and polar fragments (glycine, taurine, cysteine, and succinic/glutaric anhydride spacers), and by replacing the 3,4-methylenedioxybenzyl motif with substituted aromatic aldehydes. All target compounds were characterized by 1H/13C NMR and HR-MS and evaluated for cytotoxicity against rat aortic smooth muscle cells, calculated Log P and aqueous solubility, NO release, and phosphodiesterase type-5A (PDE5A) inhibitory activity, followed by 100 ns molecular dynamics (MD) simulations and MM/PBSA calculations on the leading analogue. Compound 18, bearing a p-methoxyphenyl group and an N-methyl amide, markedly enhanced NO release relative to tadalafil, reduced residual PDE5A activity to 38.69 ± 1.98% at 10 μM, and exhibited negligible cytotoxicity with a predicted logP of 1.53. Docking into PDE5 (PDB: 1XOZ) and MD analysis revealed a stable binding pose anchored by hydrogen bonds to Gln817 and Tyr612, reinforced by π–π stacking with Phe820 and extensive hydrophobic contacts with Leu765, Ile768, Val782, and Met816 (ΔG_bind = −9.13 ± 3.30 kcal/mol), with van der Waals contributions dominating (−41.78 ± 4.60 kcal/mol). Collectively, compound 18 emerges as a promising next-generation tadalafil-derived PDE5 inhibitor lead, and the resulting SAR picture outlines a hydrophobic-anchor-dominated optimization strategy for this scaffold.",
  "abstract_shown": true,
  "affiliations": [
    "Institute of Chemical Drugs, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China",
    "Shandong Engineering Research Center of Pharmaceutical Green Intelligent Technology, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Wentao Liu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Bin Zhang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yuping Jia"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Xiangyu Kong"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yuxiao Deng"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Xinqiang Cui"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Li Yang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Wenjie Ren"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Xuan Tang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Daizhou Zhang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Lingwen Xu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/32fjdsy5e9jhq.bib",
  "cited_by": 0,
  "doi": "10.3390/molecules31203785",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13707866/?tool=EBI",
  "id": "32fjdsy5e9jhq",
  "issns": [
    "1420-3049"
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  "landing_url": "https://www.mdpi.com/1420-3049/31/20/3785",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "QD241-441"
    ],
    [
      "openalex",
      "1312|Phosphodiesterase function and regulation"
    ]
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  "openalex": "W7223179386",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13707866/pdf/?tool=EBI",
  "pmcid": "PMC13707866",
  "pmid": null,
  "published": "2026-10-01",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/32fjdsy5e9jhq.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:42Z",
      "native_id": "10.3390/molecules31203785",
      "source": "crossref",
      "url": "https://www.mdpi.com/1420-3049/31/20/3785"
    },
    {
      "first_seen": "2026-10-30T12:21:31Z",
      "native_id": "PMC:PMC13707866",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13707866"
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    {
      "first_seen": "2026-10-31T14:21:34Z",
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Phosphodiesterase function and regulation",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Design, Synthesis, Evaluation, and Molecular Dynamics Simulation of Tadalafil Derivatives for the Treatment of Erectile Dysfunction",
  "title_text": "Design, Synthesis, Evaluation, and Molecular Dynamics Simulation of Tadalafil Derivatives for the Treatment of Erectile Dysfunction",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T14:21:34Z",
  "url": "https://research.draconitic.com/paper/32fjdsy5e9jhq",
  "venue": "Molecules",
  "versions": []
}