{
  "abstract": "Histone deacetylase 8 (HDAC8) has emerged as a promising anticancer target; however, most clinically approved hydroxamate-based HDAC inhibitors possess several limitations. A novel series of quinoxaline-based HDAC inhibitors containing a sulfur-based cyanocarbonimidodithioate non-hydroxamate zinc-binding group was designed and synthesized to overcome the selectivity and toxicity limitations of conventional hydroxamate HDAC inhibitors. A total of twenty-three quinoxaline-cyanocarbonimidodithioate derivatives (QZ 1-23) were synthesized and evaluated for HDAC8 inhibitory activity. The compounds demonstrated preferential inhibition of HDAC8 over HDAC4. Among the series, QZ-11 (IC50 = 0.3 μM) and QZ-4 (IC50 = 0.57 μM) emerged as the most promising inhibitors exhibiting favourable selectivity profiles against other tested HDAC isoforms. Both compounds demonstrated moderate to good antiproliferative activity against the IMR-32, SH-SY5Y, and FaDu cell lines. Biological studies revealed that QZ-4 and QZ-11 significantly suppressed colony formation, induced apoptosis, activated caspase-3/7, and induced G2/M phase cell-cycle arrest in IMR-32 cells, and increased acetylation of the HDAC8 substrate SMC3 without altering total SMC3 expression. Molecular docking studies suggested key interactions with HDAC8 selectivity-determining residues His142, Tyr306, and Phe152, while molecular dynamics simulations revealed stable occupancy of the catalytic pocket and persistent Zn-associated interactions throughout 100 ns trajectories. Collectively, these findings identify quinoxaline-cyanocarbonimidodithioates as a promising class of non-hydroxamate HDAC8- inhibitors and support further optimization of sulfur-based zinc-binding pharmacophores for the development of next-generation epigenetic anticancer agents.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemistry",
    "Birla Institute of Technology & Science-Pilani, Hyderabad campus, Hyderabad-500078",
    "Department of Biological Sciences",
    "Birla Institute of Technology & Science-Pilani, Hyderabad campus",
    "Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Haardtring 100, Darmstadt, Germany, 64295",
    "Department of Chemistry, School of Applied Sciences and Humanities",
    "Vignan's Foundation for Science Technology and Research University (VFSTR",
    "Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan, India, 3331"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Kosana Sai Chaitanya"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Dharani Sen"
    },
    {
      "affs": [
        4
      ],
      "name": "Markus Schweipert"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Srinuvasu Nakka"
    },
    {
      "affs": [
        7
      ],
      "name": "Muzaffar-Ur-Rehman Mohammed"
    },
    {
      "affs": [
        4
      ],
      "name": "Katja Ohlemüller"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Koshankan Chandra"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Vivek Sharma"
    },
    {
      "affs": [
        7
      ],
      "name": "Sankaranarayanan Murugesan"
    },
    {
      "affs": [
        4
      ],
      "name": "Franz-Josef Meyer-Almes"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Kondapalli Venkata Gowri Chandra Sekhar"
    },
    {
      "name": "KVG Chandrasekhar",
      "orcid": "0000-0002-2319-8297"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8qdqa88fhrjec.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15009770/v1",
  "fulltext_url": null,
  "id": "8qdqa88fhrjec",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009770/v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Histone Deacetylase Inhibitors Research"
    ]
  ],
  "openalex": "W7216037110",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15009770/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-02",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/8qdqa88fhrjec.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:21Z",
      "native_id": "10.26434/chemrxiv.15009770",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009770/v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Histone Deacetylase Inhibitors Research",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Novel Quinoxaline-Based Cyanocarbonimidodithioate Derivatives as Non-Hydroxamate Selective HDAC8 Inhibitors: Design, Synthesis, Biological Evaluation and Mechanistic Studies",
  "title_text": "Novel Quinoxaline-Based Cyanocarbonimidodithioate Derivatives as Non-Hydroxamate Selective HDAC8 Inhibitors: Design, Synthesis, Biological Evaluation and Mechanistic Studies",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:21Z",
  "url": "https://research.draconitic.com/paper/8qdqa88fhrjec",
  "venue": "ChemRxiv",
  "versions": []
}