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Abstract <p><b>Objective:</b> Malignant neoplasms remain a paramount global challenge, imposing severe socioeconomic costs and high morbidity and mortality rates worldwide. To address the urgent demand for novel therapeutics, this study focuses on the development of new heterocyclic architectures—specifically pyrazole and acyl hydrazone derivatives—designed to modulate key oncogenic signaling pathways and act as compelling chemotherapeutic candidates. <b>Methods:</b> A novel series of pyrazole and acyl hydrazone derivatives was synthesized and evaluated <i>in vitro</i> for their cytotoxic profiles against HepG2, HCT-116, MCF-7, and A549 human cancer cell lines utilizing the MTT assay, with doxorubicin serving as the reference drug. To evaluate their electronic properties and chemical stability, density functional theory (DFT) computations were performed. Furthermore, molecular docking simulations were executed against Aurora A kinase (PDB ID: 5EW9) and PDZ-binding kinase (PDB ID: 5J0A) to elucidate their binding modes and potential as targeted kinase inhibitors. <b>Results and Discussion:</b> Specifically, <b>IVd</b> and <b>Vc</b> yielded IC<sub>50</sub> values of 32.17 and 34.43 µM against HepG2, 11.37 and 13.56 µM against HCT-116, 24.39 and 27.51 µM against MCF-7, and 56.36 and 62.13 µM against A549 cells, respectively, displaying potencies comparable to or exceeding that of doxorubicin. DFT computations revealed optimized frontier molecular orbital profiles, where the calculated HOMO–LUMO energy gaps rationalized the observed chemical stability and electronic properties. In docking studies, compound <b>IVd</b> exhibited a robust binding affinity of –7.7 kcal/mol within the active pocket of Aurora A kinase, whereas <b>Vc</b> demonstrated a binding energy of –7.6 kcal/mol toward PDZ-binding kinase. <b>Conclusions:</b> Collectively, these findings underscore the potential of these dual scaffolds as targeted kinase inhibitors. The demonstrated cytotoxicity and molecular interaction profiles offer a valuable structural and electronic rationale for the design of next-generation anticancer therapeutics.</p>

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Development of Pyrazole and Acyl Hydrazone Derivatives as Potential Anticancer Agents: A Combined DFT and Molecular Docking Approach

  • 期刊论文

  • 发表日期：

    2026年8月4日

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  • Mohammed Al-Ghorbani,
  • Osama Alharbi,
  • Wael H. Alsaedi,
  • Abdel-Basit Al-Odayni,
  • Ali Alrahlah,
  • Ajay Thakur,
  • Saif H. Althagafi,
  • Munjed M. Ibrahim,
  • Ramith Ramu

摘要

Abstract

Objective: Malignant neoplasms remain a paramount global challenge, imposing severe socioeconomic costs and high morbidity and mortality rates worldwide. To address the urgent demand for novel therapeutics, this study focuses on the development of new heterocyclic architectures—specifically pyrazole and acyl hydrazone derivatives—designed to modulate key oncogenic signaling pathways and act as compelling chemotherapeutic candidates. Methods: A novel series of pyrazole and acyl hydrazone derivatives was synthesized and evaluated in vitro for their cytotoxic profiles against HepG2, HCT-116, MCF-7, and A549 human cancer cell lines utilizing the MTT assay, with doxorubicin serving as the reference drug. To evaluate their electronic properties and chemical stability, density functional theory (DFT) computations were performed. Furthermore, molecular docking simulations were executed against Aurora A kinase (PDB ID: 5EW9) and PDZ-binding kinase (PDB ID: 5J0A) to elucidate their binding modes and potential as targeted kinase inhibitors. Results and Discussion: Specifically, IVd and Vc yielded IC50 values of 32.17 and 34.43 µM against HepG2, 11.37 and 13.56 µM against HCT-116, 24.39 and 27.51 µM against MCF-7, and 56.36 and 62.13 µM against A549 cells, respectively, displaying potencies comparable to or exceeding that of doxorubicin. DFT computations revealed optimized frontier molecular orbital profiles, where the calculated HOMO–LUMO energy gaps rationalized the observed chemical stability and electronic properties. In docking studies, compound IVd exhibited a robust binding affinity of –7.7 kcal/mol within the active pocket of Aurora A kinase, whereas Vc demonstrated a binding energy of –7.6 kcal/mol toward PDZ-binding kinase. Conclusions: Collectively, these findings underscore the potential of these dual scaffolds as targeted kinase inhibitors. The demonstrated cytotoxicity and molecular interaction profiles offer a valuable structural and electronic rationale for the design of next-generation anticancer therapeutics.