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PreprintCC BYChemRxiv

Novel Quinoxaline-Based Cyanocarbonimidodithioate Derivatives as Non-Hydroxamate Selective HDAC8 Inhibitors: Design, Synthesis, Biological Evaluation and Mechanistic Studies

  • Kosana Sai Chaitanya1,2
  • Dharani Sen3,4
  • Markus Schweipert5
  • Srinuvasu Nakka6,7
  • Muzaffar-Ur-Rehman Mohammed8
  • Katja Ohlemüller5
  • Koshankan Chandra3,4
  • Vivek Sharma3,4
  • Sankaranarayanan Murugesan8
  • Franz-Josef Meyer-Almes5
  • Kondapalli Venkata Gowri Chandra Sekhar1,2
  • KVG Chandrasekhar
8 affiliations
  1. 1Department of Chemistry
  2. 2Birla Institute of Technology & Science-Pilani, Hyderabad campus, Hyderabad-500078
  3. 3Department of Biological Sciences
  4. 4Birla Institute of Technology & Science-Pilani, Hyderabad campus
  5. 5Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Haardtring 100, Darmstadt, Germany, 64295
  6. 6Department of Chemistry, School of Applied Sciences and Humanities
  7. 7Vignan's Foundation for Science Technology and Research University (VFSTR
  8. 8Department of Pharmacy, Birla Institute of Technology and Science, Pilani Campus, Pilani, Rajasthan, India, 3331
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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.

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Cite

BibTeXRIS
BibTeX
@misc{chaitanya2026novel,
  title = {{Novel Quinoxaline-Based Cyanocarbonimidodithioate Derivatives as Non-Hydroxamate Selective HDAC8 Inhibitors: Design, Synthesis, Biological Evaluation and Mechanistic Studies}},
  author = {Kosana Sai Chaitanya and Dharani Sen and Markus Schweipert and Srinuvasu Nakka and Muzaffar-Ur-Rehman Mohammed and Katja Ohlemüller and Koshankan Chandra and Vivek Sharma and Sankaranarayanan Murugesan and Franz-Josef Meyer-Almes and Kondapalli Venkata Gowri Chandra Sekhar and KVG Chandrasekhar},
  howpublished = {ChemRxiv},
  year = {2026},
  month = oct,
  doi = {10.26434/chemrxiv.15009770/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009770/v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Novel Quinoxaline-Based Cyanocarbonimidodithioate Derivatives as Non-Hydroxamate Selective HDAC8 Inhibitors: Design, Synthesis, Biological Evaluation and Mechanistic Studies
AU  - Kosana Sai Chaitanya
AU  - Dharani Sen
AU  - Markus Schweipert
AU  - Srinuvasu Nakka
AU  - Muzaffar-Ur-Rehman Mohammed
AU  - Katja Ohlemüller
AU  - Koshankan Chandra
AU  - Vivek Sharma
AU  - Sankaranarayanan Murugesan
AU  - Franz-Josef Meyer-Almes
AU  - Kondapalli Venkata Gowri Chandra Sekhar
AU  - KVG Chandrasekhar
PY  - 2026
DA  - 2026/10/02
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15009770/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009770/v1
AB  - 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.
ER  -