Synthesis, In-Vitro Evaluation, and Computational Investigation of Salicylic Hydrazide Derivatives as Potential Tyrosine Kinase–Targeted Anticancer Agents
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Keywords:
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Anticancer Drug Discovery, Microwave-Assisted Synthesis, Molecular Docking, Network Pharmacology, Salicylic Hydrazides, Tyrosine Kinase Inhibition
Abstract
A series of N2-acyl salicylic hydrazides (S2-S6) and N-(substituted benzylidene) salicylic hydrazides (S7-S9) were synthesized from 2-hydroxybenzohydrazide (S1), using both microwave irradiation and conventional methods, and tested for its in vitro anticancer activity against human lung cancer cell, A549. The salicylic hydrazides were successfully synthesized in good yields (79–98%) and the in-vitro study results indicated that 3,4-dichloro-N'-(2-hydroxybenzoyl)benzohydrazide (S5) was most active among the tested compounds (IC50 value of 68.75 µM). In this work, we applied an integrated approach combining network pharmacology and computational analysis to explore how salicylic hydrazide derivatives affect tyrosine kinase–related pathways. The in-silico findings were in agreement with the in vitro results, indicating that compound S5 produced a docking score of –6.53468 kcal/mol. The findings of this research are expected to support further development toward identifying promising anticancer drug candidates derived from salicylic hydrazide derivatives.
References
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Mondal, S., S. Vishakha, K. D. Kajal, S. K. Wahan, B. D. Kurmi, and P. Patel (2023). Current Trends in the Development of EGFR Inhibitors as Promising Anticancer Agents: SAR and Synthetic Studies from (2010–2020). Current Organic Chemistry, 27(1); 2–27.
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Nikolova-Mladenova, B., G. Momekov, Z. Zhivkova, and I. Doytchinova (2023). Design, Synthesis and Cytotoxic Activity of Novel Salicylaldehyde Hydrazones against Leukemia and Breast Cancer. International Journal of Molecular Sciences, 24(8); 7352.
Saha, A., R. Kumar, R. Kumar, and C. Devakumar (2010). Development and Assessment of Green Synthesis of Hydrazides. ChemInform, 41(34); 526–531.
Scardoni, G., G. Tosadori, M. Faizan, F. Spoto, F. Fabbri, and C. Laudanna (2014). Biological Network Analysis with CentiScaPe: Centralities and Experimental Dataset Integration. F1000Research, 3; 139.
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Singh, I. P., S. Gurtu, A. Kumar, J. N. Sinha, K. P. Bhargava, and K. Shanker (1984). Antiinflammatory Activities of Compounds Derived from Salicylic and Benzoic Acids. Archiv der Pharmazie, 317(7); 609–614.
Sudhesh Dev, S., S. A. Zainal Abidin, R. Farghadani, I. Othman, and R. Naidu (2021). Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer. Frontiers in Pharmacology, 12; 772510.
Sulistyowaty, M. I., G. Putra, T. Budiati, and K. Matsunami (2020). Synthesis, In Vitro Anticancer Activity and In Silico Study of Some Benzylidene Hydrazide Derivatives. Key Engineering Materials, 840; 277–283.
Sulistyowaty, M. I., R. Widyowati, G. S. Putra, T. Budiati, and K. Matsunami (2021). Synthesis, ADMET Predictions, Molecular Docking Studies, and In-Vitro Anticancer Activity of Some Benzoxazines against A549 Human Lung Cancer Cells. Journal of Basic and Clinical Physiology and Pharmacology, 32(4); 385–392.
Terracciano, S., G. Lauro, A. Russo, M. C. Vaccaro, A. Vassallo, M. De Marco, and I. Bruno (2018). Discovery and Synthesis of the First Selective BAG Domain Modulator of BAG3 as an Attractive Candidate for the Development of a New Class of Chemotherapeutics. Chemical Communications, 54(55); 7613–7616.
Torres-Avilés, R., G. Gutiérrez, M. Muñoz, and M. Caniupán (2024). Skyline Query over K2-Tree Compact Data Structure. In 2024 43rd International Conference of the Chilean Computer Science Society (SCCC). pages 1–8.
Wang, L., W. Qin, X. Tang, W. Dou, and W. Liu (2011). Development and Applications of Fluorescent Indicators for Mg2+ and Zn2+. The Journal of Physical Chemistry A, 115(9); 1609–1616.
Wilcken, R., M. O. Zimmermann, A. Lange, A. C. Joerger, and F. M. Boeckler (2013). Principles and Applications of Halogen Bonding in Medicinal Chemistry and Chemical Biology. Journal of Medicinal Chemistry, 56(4); 1363–1388.
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Zhang, Q., Y. Queneau, and L. Soulère (2020). Biological Evaluation and Docking Studies of New Carbamate, Thiocarbamate, and Hydrazide Analogues of Acyl Homoserine Lactones as Vibrio fischeri-Quorum Sensing Modulators. Biomolecules, 10(3); 455.
Zhao, H. and T. R. Burke (1997). Pentafluorophenyl Ester Activation for the Preparation of N,N’-Diaroylhydrazines. Tetrahedron, 53(12); 4219–4230.
Abdelfattah, A. M., A. E. M. Mekky, and S. M. H. Sanad (2022). Synthesis, Antibacterial Activity and in Silico Study of New Bis(1,3,4-oxadiazoles). Synthetic Communications, 52(11–12); 1421–1440.
Altıntop, M. D., A. Özdemir, G. Turan-Zitouni, S. Ilgın, Ö. Atlı, G. İşcan, and Z. A. Kaplancıklı (2012). Synthesis and Biological Evaluation of Some Hydrazone Derivatives as New Anticandidal and Anticancer Agents. European Journal of Medicinal Chemistry, 58; 299–307.
Araujo, J. and C. Logothetis (2010). Dasatinib: A Potent SRC Inhibitor in Clinical Development for the Treatment of Solid Tumors. Cancer Treatment Reviews, 36(6); 492–500.
Ashburner, M., C. A. Ball, J. A. Blake, D. Botstein, H. Butler, J. M. Cherry, and G. Sherlock (2000). Gene Ontology: Tool for the Unification of Biology. Nature Genetics, 25(1); 25–29.
Baashen, M. A. (2021). Synthesis of N,N’-Diacylhydrazines and Their Use in Various Synthetic Transformations. Current Organic Chemistry, 25(12); 1394–1403.
Carbon, S., E. Douglass, B. M. Good, D. R. Unni, N. L. Harris, C. J. Mungall, and J. Elser (2021). The Gene Ontology Resource: Enriching a GOld Mine. Nucleic Acids Research, 49(D1); D325–D334.
Chaudhary, S., P. Chattopadhyay, A. K. Wahi, M. Didel, and V. Dahiya (2010). Synthesis and Study of Antibacterial and Antifungal Activity of Novel 2-(5-Substituted Methylamino 1,3,4-thiadiazol-2-yl)phenols. Journal of Chemical and Pharmaceutical Research, 2(1); 47–52.
Fatriani, R., F. A. K. Pratiwi, A. Annisa, D. A. Septaningsih, S. A. Aziz, I. Miladiyah, and W. A. Kusuma (2024). Unveiling the Anti-Obesity Potential of Kemuning (Murraya paniculata): A Network Pharmacology Approach. PLOS ONE, 19(8); e0305544.
Hassan, A. A., Y. R. Ibrahim, and A. M. Shawky (2008). Reactions of Substituted Carbohydrazides with Electron-Poor Olefins. Zeitschrift für Naturforschung B, 63(8); 998–1004.
Hernandes, M. Z., S. M. Cavalcanti, D. R. Moreira, W. F. de Azevedo Junior, and A. C. Leite (2010). Halogen Atoms in the Modern Medicinal Chemistry: Hints for the Drug Design. Current Drug Targets, 11(3); 303–314.
Hopkins, A. L. (2008). Network Pharmacology: The Next Paradigm in Drug Discovery. Nature Chemical Biology, 4(11); 682–690.
Kajal, K., G. Singh, T. Pradhan, D. Bhurta, and V. Monga (2022). The Medicinal Perspective of 2,4 Thiazolidinediones Based Ligands as Antimicrobial, Antitumor and Antidiabetic Agents: A Review. Archiv der Pharmazie, 355(9).
Kanehisa, M., M. Furumichi, Y. Sato, M. Kawashima, and M. Ishiguro-Watanabe (2023). KEGG for Taxonomy-Based Analysis of Pathways and Genomes. Nucleic Acids Research, 51(D1); D587–D592.
Levinson, N. M. and S. G. Boxer (2014). A Conserved Water Mediated Hydrogen Bond Network Defines Bosutinib’s Kinase Selectivity. Nature Chemical Biology, 10(2); 127–132.
Li, L. and S. Kar (2025). Leveraging Network Pharmacology for Drug Discovery: Integrative Approaches and Emerging Insights. Medicine in Drug Discovery, 27; 100220.
Lian, L., X.-L. Li, M.-D. Xu, X.-M. Li, M.-Y. Wu, Y. Zhang, and M. Jiang (2019). VEGFR2 Promotes Tumorigenesis and Metastasis in a Pro-Angiogenic-Independent Way in Gastric Cancer. BMC Cancer, 19(1); 183.
Lipinski, C. A., F. Lombardo, B. W. Dominy, and P. J. Feeney (2001). Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Advanced Drug Delivery Reviews, 46(1–3); 3–26.
Martellucci, S., L. Clementi, S. Sabetta, V. Mattei, L. Botta, and A. Angelucci (2020). Src Family Kinases as Therapeutic Targets in Advanced Solid Tumors: What We Have Learned so Far. Cancers, 12(6); 1448.
Mihailović, N., V. Marković, I. Z. Matić, N. S. Stanisavljević, Ž. S. Jovanović, S. Trifunović, and L. Joksović (2017). Synthesis and Antioxidant Activity of 1,3,4-Oxadiazoles and Their Diacylhydrazine Precursors Derived from Phenolic Acids. RSC Advances, 7(14); 8550–8560.
Mogilaiah, K., E. Anitha, K. S. Kumar, and R. S. Prasad (2011). A Convenient and Simple Transformation of Acid Hydrazides to N,N’-Diacylhydrazines with Hg(OAc)2 under Solid State Conditions. ChemInform, 42(16).
Mondal, S., S. Vishakha, K. D. Kajal, S. K. Wahan, B. D. Kurmi, and P. Patel (2023). Current Trends in the Development of EGFR Inhibitors as Promising Anticancer Agents: SAR and Synthetic Studies from (2010–2020). Current Organic Chemistry, 27(1); 2–27.
Mutiah, R., M. S. D. Briliana, A. R. A. Ahmad, B. Fauziyah, N. A. Janaloka, and A. Suryadinata (2024). Network Pharmacology and Component Analysis Integrated Study to Uncovers the Molecular Mechanisms of Lansium parasiticum Bark Extract in Colon Cancer Treatment. Science and Technology Indonesia, 9(2); 314–324.
Nikolova-Mladenova, B., G. Momekov, Z. Zhivkova, and I. Doytchinova (2023). Design, Synthesis and Cytotoxic Activity of Novel Salicylaldehyde Hydrazones against Leukemia and Breast Cancer. International Journal of Molecular Sciences, 24(8); 7352.
Saha, A., R. Kumar, R. Kumar, and C. Devakumar (2010). Development and Assessment of Green Synthesis of Hydrazides. ChemInform, 41(34); 526–531.
Scardoni, G., G. Tosadori, M. Faizan, F. Spoto, F. Fabbri, and C. Laudanna (2014). Biological Network Analysis with CentiScaPe: Centralities and Experimental Dataset Integration. F1000Research, 3; 139.
Selaković, S., M. V. Rodić, I. Novaković, I. Z. Matić, T. Stanojković, A. Pirković, and M. Šumar-Ristović (2024). Cu(II) Complexes with a Salicylaldehyde Derivative and α-Diimines as Co-Ligands: Synthesis, Characterization, Biological Activity. Experimental and Theoretical Approach. Dalton Transactions, 53(6); 2770–2788.
Sigismund, S., D. Avanzato, and L. Lanzetti (2018). Emerging Functions of the EGFR in Cancer. Molecular Oncology, 12(1); 3.
Singh, I. P., S. Gurtu, A. Kumar, J. N. Sinha, K. P. Bhargava, and K. Shanker (1984). Antiinflammatory Activities of Compounds Derived from Salicylic and Benzoic Acids. Archiv der Pharmazie, 317(7); 609–614.
Sudhesh Dev, S., S. A. Zainal Abidin, R. Farghadani, I. Othman, and R. Naidu (2021). Receptor Tyrosine Kinases and Their Signaling Pathways as Therapeutic Targets of Curcumin in Cancer. Frontiers in Pharmacology, 12; 772510.
Sulistyowaty, M. I., G. Putra, T. Budiati, and K. Matsunami (2020). Synthesis, In Vitro Anticancer Activity and In Silico Study of Some Benzylidene Hydrazide Derivatives. Key Engineering Materials, 840; 277–283.
Sulistyowaty, M. I., R. Widyowati, G. S. Putra, T. Budiati, and K. Matsunami (2021). Synthesis, ADMET Predictions, Molecular Docking Studies, and In-Vitro Anticancer Activity of Some Benzoxazines against A549 Human Lung Cancer Cells. Journal of Basic and Clinical Physiology and Pharmacology, 32(4); 385–392.
Terracciano, S., G. Lauro, A. Russo, M. C. Vaccaro, A. Vassallo, M. De Marco, and I. Bruno (2018). Discovery and Synthesis of the First Selective BAG Domain Modulator of BAG3 as an Attractive Candidate for the Development of a New Class of Chemotherapeutics. Chemical Communications, 54(55); 7613–7616.
Torres-Avilés, R., G. Gutiérrez, M. Muñoz, and M. Caniupán (2024). Skyline Query over K2-Tree Compact Data Structure. In 2024 43rd International Conference of the Chilean Computer Science Society (SCCC). pages 1–8.
Wang, L., W. Qin, X. Tang, W. Dou, and W. Liu (2011). Development and Applications of Fluorescent Indicators for Mg2+ and Zn2+. The Journal of Physical Chemistry A, 115(9); 1609–1616.
Wilcken, R., M. O. Zimmermann, A. Lange, A. C. Joerger, and F. M. Boeckler (2013). Principles and Applications of Halogen Bonding in Medicinal Chemistry and Chemical Biology. Journal of Medicinal Chemistry, 56(4); 1363–1388.
Xie, Z., A. Bailey, M. V. Kuleshov, D. J. B. Clarke, J. E. Evangelista, S. L. Jenkins, and A. Ma’ayan (2021). Gene Set Knowledge Discovery with Enrichr. Current Protocols, 1(3); e90.
Zhang, Q., Y. Queneau, and L. Soulère (2020). Biological Evaluation and Docking Studies of New Carbamate, Thiocarbamate, and Hydrazide Analogues of Acyl Homoserine Lactones as Vibrio fischeri-Quorum Sensing Modulators. Biomolecules, 10(3); 455.
Zhao, H. and T. R. Burke (1997). Pentafluorophenyl Ester Activation for the Preparation of N,N’-Diaroylhydrazines. Tetrahedron, 53(12); 4219–4230.
Authors
Sulistyowaty, M., Tri Widiandani, Albertus Aditya Setiawan, Seow Lay Jing, Neny Purwitasari, Ferlinahayati, Dwi Setyawan, Galih Satrio Putra, & Anastasia Wheni Indrianingsih. (2026). Synthesis, In-Vitro Evaluation, and Computational Investigation of Salicylic Hydrazide Derivatives as Potential Tyrosine Kinase–Targeted Anticancer Agents. Science and Technology Indonesia, 11(2), 609–620. https://doi.org/10.26554/sti.2026.11.2.609-620
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