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Purpose <p>Poly(ADP-ribose) polymerase-1 (PARP-1) is a validated therapeutic target in BRCA-mutated prostate cancer due to its role in DNA repair. This study aimed to design, synthesize, and evaluate quinoxaline-based derivatives as potential PARP-1 inhibitors with anticancer activity.</p> Methods <p>A rational design strategy targeting the NAD⁺ nicotinamide (NI) sub-pocket guided the synthesis of ten quinoxaline derivatives (Q4a–Q4j). The synthesis involved quinoxaline core formation, sulfonation, hydrazide derivatization, and coupling with substituted benzoic acids. Structures were confirmed using FT-IR, EI-MS, and NMR spectroscopy. Cytotoxicity against BRCA1-mutated PC-3 cells was assessed by MTT assay. Molecular docking (AutoDock Vina), <i>in silico </i>ADMET (pKCSM) analyses and Molecular dynamic simulation (MDS) were performed.</p> Results <p>All compounds demonstrated moderate antiproliferative activity against PC-3 cells, with IC₅₀ values ranging from 45.86 to 101.01&#xa0;µg/mL. Docking studies revealed favorable binding orientations within the PARP-1 catalytic NI sub-pocket, supported by hydrogen bonding and π–π stacking interactions. ADMET predictions indicated acceptable drug-likeness properties.</p> Conclusion <p>The synthesized quinoxaline derivatives exhibit promising antiproliferative activity with computationally supported PARP-1 binding potential. However, direct enzymatic inhibition studies are required to confirm target-specific activity and further validate their therapeutic relevance.</p>

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Design, Synthesis, and Biological Evaluation of New Quinoxaline Derivatives for Treatment of Prostate Cancer

  • 期刊论文

  • 发表日期：

    2026年3月16日

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  • Anish Kumar,
  • Drashti Shah,
  • Ghanshyam Parmar,
  • Ashish Patel

摘要

Purpose

Poly(ADP-ribose) polymerase-1 (PARP-1) is a validated therapeutic target in BRCA-mutated prostate cancer due to its role in DNA repair. This study aimed to design, synthesize, and evaluate quinoxaline-based derivatives as potential PARP-1 inhibitors with anticancer activity.

Methods

A rational design strategy targeting the NAD⁺ nicotinamide (NI) sub-pocket guided the synthesis of ten quinoxaline derivatives (Q4a–Q4j). The synthesis involved quinoxaline core formation, sulfonation, hydrazide derivatization, and coupling with substituted benzoic acids. Structures were confirmed using FT-IR, EI-MS, and NMR spectroscopy. Cytotoxicity against BRCA1-mutated PC-3 cells was assessed by MTT assay. Molecular docking (AutoDock Vina), in silico ADMET (pKCSM) analyses and Molecular dynamic simulation (MDS) were performed.

Results

All compounds demonstrated moderate antiproliferative activity against PC-3 cells, with IC₅₀ values ranging from 45.86 to 101.01 µg/mL. Docking studies revealed favorable binding orientations within the PARP-1 catalytic NI sub-pocket, supported by hydrogen bonding and π–π stacking interactions. ADMET predictions indicated acceptable drug-likeness properties.

Conclusion

The synthesized quinoxaline derivatives exhibit promising antiproliferative activity with computationally supported PARP-1 binding potential. However, direct enzymatic inhibition studies are required to confirm target-specific activity and further validate their therapeutic relevance.