Email this article 
Multifaceted Applications of Pyrazole-Based Tetradentate Ligand Coordinated with Transition Metals (Fe, Zn, Co, Cu): Synthesis, Characterization, Catalysis, Antimicrobial Activity, ADMET, and Molecular Docking Insights
Abstract
This study reports the synthesis of a pyrazole-based tetradentate ligand and its coordination with transition metals (iron, zinc, cobalt, and copper) to evaluate catalytic and antimicrobial properties. The ligand was synthesized via condensation reactions and characterized using spectroscopic methods. Coordination with metal salts generated mono- and dinuclear complexes, which were tested for catechol oxidation activity, antimicrobial potential, pharmacokinetic profiles, and molecular docking with P-glycoprotein. Findings revealed that iron complexes, especially the diiron variant, exhibited the highest catalytic efficiency. The free ligand showed strong antifungal activity, while selected metal complexes displayed selective antibacterial effects. These results indicate that metal coordination modulates electronic and structural properties, enhancing redox activity and biological performance. The study provides insights into designing multifunctional compounds for catalytic and therapeutic applications.
Keywords
Full Text:
PDFReferences
Chougule, M. A., Pawar, S. G., Godse, P. R., Mulik, R. N., and Sen, S. (2011). Synthesis and characterization of polypyrrole (PPy) thin films. Scientific Notes Letters, 1(1), 6–10.
Ambarwati, N. S. S., Sukma, N. T., Desmiaty, A. A. Y., Budi, M. A. S., and Ahmad, I. (2024). Molecular docking studies and ADME Tox prediction of phytocompounds from Merremia peltata as a potential anti alopecia treatment. Journal of Advanced Pharmaceutical Technology & Research, 15(1), 8–12.
Claiborne, A., and Fridovich, I. (2020). Chemical and enzymatic intermediates in the peroxidation of o-dianisidine by horseradish peroxidase. Educational Activity Programs for Older Adults, 18, 2324–2329.
Rydosz, A. (2018). The use of copper oxide thin films in gas-sensing applications. Coatings, 8(12), 425.
Fayomi, O. S. I., and Popoola, A. P. I. (2015). Anti-corrosion properties and structural characteristics of fabricated ternary coatings. Surface Engineering and Applied Electrochemistry, 51(1), 76–84.
Ouadi, Y. E., Bouratoua, A., Bouyenzer, A., Kabouche, Z., Touzani, R., El Msellem, H., Hammouti, B., and Chetouani, A. (2015). Effect of Athamanta sicula oil on inhibition of mild steel corrosion in 1M HCl. Scholars Research Library, 7(March), 103–111.
Bahriz, H., and Bouras, N. (2020). Study of Bayoud’s disease and the varietal behavior of the date palm against Fusarium oxysporum f. sp. albedinis in the Mzab Valley A. African Review of Science, Technology and Development, 5(1), 41–60.
Belfilali, I., and Roisnel, T. (2024). Catecholase activity assessment of in-situ copper complexes derived from a novel Schiff base ligand. Inorganic Chemistry Communications, 164(II), 1–15.
Radi, S., Salhi, S., and Radi, A. (2009). Synthesis and preliminary biological activity of some new pyrazole derivatives as acyclonucleoside analogues. Letters in Drug Design & Discovery, 7(1), 27–30.
Kaddouri, Y., Benabbes, R., Ouahhoud, S., Abdellattif, M., Hammouti, B., and Touzani, R. (2022). An insight into all tested small molecules against Fusarium oxysporum f. sp. albedinis: A comparative review. Molecules, 27(9), 1–21.
Karrouchi, K., Charkaoui, Y., Benlafya, K., Ramli, Y., Taoufik, J., Radi, S., & Ansar, M. (2013). Synthesis, characterization and preliminary biological activity of some new pyrazole carbohydrazide derivatives. Journal of Chemical and Pharmaceutical Research, 5(3), 1–6.
Boutaybi, M. E., Bouroumane, N., Azzouzi, M., Aaddouz, M., Bacroume, S., El Miz, M., and Touzani, R. (2023). Synthesis, characterization, DFT, and thermogravimetric analysis of neutral Co(II)/pyrazole complex, catalytic activity toward catecholase and phenoxazinone oxidation. Crystals, 13, 155.
Messali, M., Ati, R. E., Touzani, R., Aouad, M. R., and Warad, I. (2018). Crystal structure of the coordination polymer catena-poly [chlorido-{μ2-2-(((3, 5-dimethyl-1 H-pyrazol-1-yl) methyl) amino)-3-hydroxybutanoato-κ4 N, N, O: O′} copper (II)], C11H16ClCuN2O3. Zeitschrift für Kristallographie-New Crystal Structures, 233(3), 493-494.
Setifi, F., Moon, D., Koen, R., Setifi, Z., Lamsayah, M., and Touzani, R. (2016). Crystal structure of bis(azido-κN)bis(quinolin-8-amine-κ²N,N′)iron(II). Acta Crystallographica Section E: Crystallographic Communications, 72, 1488–1491.
Titi, A., Messali, M., Touzani, R., Fettouhi, M., Zarrouk, A., Al-Zaqri, N., and Warad, I. (2020). Synthesis of Novel Tetra (µ3-Methoxo) Bridged with [Cu (II)-O-Cd (II)] Double-Open-Cubane Cluster: XRD/HSA-Interactions, Spectral and Oxidizing Properties. International Journal of Molecular Sciences, 21(22), 8787.
Benzai, A., Derridj, F., El Ati, R., El Kodadi, M., Touzani, R., Aouniti, A., Hammouti, B., Ben Hadda, T., and Doucet, H. (2019). Studies of catecholase activities of N-donor bidentates ligands derivated from benzoxazole with copper (II) salts. Moroccan Journal of Chemistry, 7(2), 401–409.
Zeghib, L. S., Kabouche, A., Semra, Z., Smati, F., Touzani, R., and Kabouche, Z. (2013). Composition, antibacterial and antioxidant activity of the essential oil of Thymus numidicus Poiret from Constantine (Algeria). Der Pharmacia Lettre, 5, 206–210.
Touzani, R., Ramdani, A., Ben-Hadda, T., El Kadiri, S., Maury, O., Le Bozec, H., and Dixneuf, P. H. (2001). Efficient synthesis of new nitrogen donor containing tripods under microwave irradiation and without solvent. Synthetic Communications, 31(9), 1315–1321.
Várnagy, K., Bóka, B., Sóvágó, I., Sanna, D., Marras, P., and Micera, G. (1998). Potentiometric and spectroscopic studies on the copper(II) and nickel(II) complexes of tripeptides of methionine. Inorganica Chimica Acta, 275–276, 440–446.
Go, Y. B., Wang, X., Anokhina, E. V., and Jacobson, A. J. (2004). A chain of changes: Influence of noncovalent interactions on the one-dimensional structures of nickel(II) dicarboxylate coordination polymers with chelating aromatic amine ligands. Inorganic Chemistry, 43(17), 5360–5367.
Amundsen, A. R., Whelan, J., and Bosnich, B. (1977). Biological analogues: On the nature of the binding sites of copper-containing proteins. Journal of the American Chemical Society, 99(20), 6730–6739.
Aust, S. D., Morehouse, L. A., and Thomas, C. E. (1985). Role of metals in oxygen radical reactions. Journal of Free Radicals in Biology and Medicine, 1(1), 3–25.
Moiseeva, A. A., and Butin, K. P. (2005). Complexation in a 5-acylpyrimidine-4-thione–aliphatic diamine–metal(II) chloride system (M = Ni or Co): The molecular structure of fac tris(5-acetyl-2,4-dimethylpyrimidine-6-thiolato)cobalt(III). Russian Journal of Coordination Chemistry, 54(12), 2757–2770.
Groysman, S., and Holm, R. H. (2009). Biomimetic chemistry of iron, nickel, molybdenum, and tungsten in sulfur-ligated protein sites. Biochemistry, 48(11), 2310–2320.
Holland, P. L., Tolman, W. B., & Se, P. S. (2000). A structural model of the type 1 copper protein active site. Journal of the American Chemical Society, 1(II), 6331–6332.
Manessi-Zoupa, E., Perlepes, S. P., Hondrellis, V., and Tsangaris, J. M. (1994). Transition metal complexes of N-(2-benzamide)pyridine-2′-carboxamide: Preparation and characterization in the solid state. Journal of Inorganic Biochemistry, 55(3), 217–233.
Prousek, J. (2007). Fenton chemistry in biology and medicine. Pure and Applied Chemistry, 79(12), 2325–2338.
Yassine, K., Abrigach, F., Ouahhoud, S., Benabbes, R., El Kodadi, M., Alsalme, A., Al-Zaqri, N., Warad, I., and Touzani, R. (2020). Mono-alkylated ligands based on pyrazole and triazole derivatives tested against Fusarium oxysporum f. sp. albedinis. Frontiers in Chemistry, 8, 1–18.
Gupta, R., Raza, A., Singh, S. K., Kaur, J., and Wadhwa, P. (2024). Computational evaluation of ADMET properties and molecular docking studies on cryptolepine analogs as inhibitors of HIV integrase. Current Signal Transduction Therapy, 19, 1–26.
Gu, Y., Yu, Z., Wang, Y., Chen, L., Lou, C., Yang, C., Li, W., Liu, G., and Tang, Y. (2024). AdmetSAR3.0: A comprehensive platform for exploration, prediction and optimization of chemical ADMET properties. Nucleic Acids Research, 52(April), W432–W438.
Masoud, M. S., Yacout, G. A., Abd-El-Khalek, B. A., and Ramadan, A. M. (2023). Synthesis, physicochemical characterization, biological assessment, and molecular docking study of some metal complexes of alloxan and ninhydrin as alterdentate ligands. Journal of Inorganic and Organometallic Polymers and Materials, 33(8), 2252–2269.
El Moussaoui, A., Jawhari, F. Z., Almehdi, A. M., Elmsellem, H., Benbrahim, K. F., Bousta, D., and Bari, A. (2019). Antibacterial, antifungal and antioxidant activity of total polyphenols of Withania frutescens. Bioorganic Chemistry, 93, 103337.
Abdel Rahman, S. M., Abd-Ellatif, S. A., Deraz, S. F., and Khalil, A. A. (2011). Antibacterial activity of some wild medicinal plants collected from western Mediterranean coast, Egypt: Natural alternatives for infectious disease treatment. African Journal of Biotechnology, 10(52), 10733–10743.
Diass, K., Merzouki, M., Elfazazi, K., Azzouzi, H., Challioui, A., Azzaoui, K., Hammouti, B., et al. (2023). Essential oil of Lavandula officinalis: Chemical composition and antibacterial activities. Plants, 12, 1571.
Bouammali, H., Zraibi, L., Ziani, I., Merzouki, M., Bourassi, L., Fraj, E., and Challioui, A.. (2024). Rosemary as a potential source of natural antioxidants and anticancer agents: A molecular docking study. Plants, 13, 1–18.
Nakajima, Y., Takeshita, T., and Jheng, N. Y. (2021). Metal-ligand cooperation behaviour of Fe and Co complexes bearing a tetradentate phenanthroline-based PNNP ligand. Dalton Transactions, 50(22), 7532–7536.
Sogukomerogullari, H. G., Yalçin, Ş. P., Ceylan, Ü., Aytar, E., Aygün, M., Richeson, D. S., and Sönmez, M. (2019). Synthesis of Fe and Cu metal complexes derived from ‘SNS’ pincer type ligands and their efficient catalyst precursors for the chemical fixation of CO₂. Journal of Chemical Sciences, 131(4), 53.
Holm, R. H., Kennepohl, P., and Solomon, E. I. (1996). Structural and functional aspects of metal sites in biology. Chemical Reviews, 96(7), 2239–2314.
Ibers, J. A., and Holm, R. H. (1980). Modeling coordination sites in N-Zn-. Science, 209(4453), 223–235.
Jazdzewski, B. A., Holland, P. L., Pink, M., Young, V. G., Spencer, D. J. E., & Tolman, W. B. (2001). Three-coordinate copper(II)-phenolate complexes. Inorganic Chemistry, 40(24), 6097–6107.
Knoblauch, S., Benedix, R., Ecke, M., Gelbrich, T., Sieler, J., Somoza, F., and Hennig, H. (1999). Synthesis, crystal structure, spectroscopy, and theoretical investigations of tetrahedrally distorted copper(II) chelates with [CuN2S2] coordination sphere. European Journal of Inorganic Chemistry, (8), 1393–1403.
Li, Y., Li, Z., Liu, Y., Dong, X., and Cui, Y. (2012). Synthesis, crystal structures, and urease inhibition studies of two new Schiff-base copper complexes derived from n-butylamine. Journal of Coordination Chemistry, 65(1), 19–27.
Raza, A., Chaudhary, J., Khan, A. A., Singh, M., Kumar, D., Malik, A., and Wadhwa, P. (2024). Exploring molecular interactions and ADMET profiles of novel MAO-B inhibitors: Toward effective therapeutic strategies for neurodegenerative disorders. Future Journal of Pharmaceutical Sciences, 10, 1–11.
Niu, Z., Xiao, X., Wu, W., Cai, Q., Jiang, Y., Jin, W., and Wang, M. (2024). PharmaBench: Enhancing ADMET benchmarks with large language models. Scientific Data, 11(1), 1–16.
El Mrayej, H., En-Nabety, G., Ettahiri, W., Jghaoui, M., Sabbahi, R., Hammouti, B., Rais, Z. and Taleb, M. (2025). Triazolopyrimidine derivatives: A comprehensive review of their synthesis, reactivity, biological properties, and molecular docking studies. Indonesian Journal of Science and Technology, 10(1), 41-74.
Merzouki, M., Khibech, O., Fraj, E., Bouammali, H., Bourhou, C., Hammouti, B., Bouammali, B., and Challioui, A. (2025). Computational engineering of malonate and tetrazole derivatives targeting SARS-CoV-2 main protease: Pharmacokinetics, docking, and molecular dynamics insights to support the sustainable development goals (SDGs), with a bibliometric analysis. Indonesian Journal of Science and Technology, 10(2), 399-418.
Alshahateet, S.F., Al-Trawneh, S.A., Hidaoui, S., Mohammed, E., Zerrouk, M., Al-Saraireh, Y.M., Al-Tawarh, W.M., Hareedy, M.S., Al-Abadleh, A.A., Alshahateet, T.S., Azzaoui, K., Hammouti, B., and Warad, I. (2026). Structural characterization, Hirshfield surface analysis, and molecular docking of novel diquinoline derivatives as anti-tumor agents. Indonesian Journal of Science and Technology, 11(1), 127-148.
Mohanasundaram, S., Karthikeyan, P., Sampath, V., Anbazhagan, M., Prabhu, S. V., Khaled, J. M., and Thiruvengadam, M. (2024). Molecular docking, dynamics simulations, ADMET, and DFT calculations: Combined in silico approach to screen natural inhibitors of 3CL and PL proteases of SARS-CoV-2. Cellular Microbiology, 2024, 1–19.
Hadda, T. B., Rastija, V., AlMalki, F., Titi, A., Touzani, R., Mabkhot, Y. N., Khalid, S., Zarrouk, A., and Siddiqui, B. S. (2019). Petra/Osiris/Molinspiration and molecular docking analyses of 3-hydroxy-indolin-2-one derivatives as potential antiviral agents. Current Computer-Aided Drug Design, 16, 1–11.
Titi, A., Messali, M., Touzani, R., Fettouhi, M., Zarrouk, A., Al-Zaqri, N., Alsalme, A., Alharthi, F. A., Alsyahi, A., and Warad, I. (2020). Synthesis of novel tetra (µ₃-methoxo) bridged [Cu(II)-O-Cd(II)] double-open-cubane cluster: XRD, spectral and oxidizing properties. International Journal of Molecular Sciences, 21, 8787.
Dascălu, D., Roman, D. L., Filip, M., Ciorsac, A., and Ostafe, V. (2020). Solubility and ADMET profiles of short oligomers of lactic acid. International Journal of Molecular Sciences, 8(4), 425–436.
Moiseeva, A. A., and Butin, K. P. (2005). Complexation in a 5-acylpyrimidine-4-thione–aliphatic diamine–metal(II) chloride system (M = Ni or Co): The molecular structure of fac tris(5-acetyl-2,4-dimethylpyrimidine-6-thiolato)cobalt(III). Russian Journal of Coordination Chemistry, 54(12), 2757–2770.
Hendrarti, W., Umar, A.H., Syahruni, R., Rafi, M., and Kusuma, W.A. (2024). Deciphering the mechanism of action cosmos caudatus compounds against breast neoplasm: A combination of pharmacological networking and molecular docking approach with bibliometric analysis. Indonesian Journal of Science and Technology, 9(2), 527-556.
Lu, S. Y., Jiang, Y. J., Lv, J., Wu, T. X., Yu, Q. S., and Zhu, W. L. (2010). Molecular docking and molecular dynamics simulation studies of GPR40 receptor–agonist interactions. Journal of Molecular Graphics and Modelling, 28(8), 766-774.
Erdogan, T. (2021). DFT, molecular docking and molecular dynamics simulation studies on some newly introduced natural products for their potential use against SARS-CoV-2. Journal of molecular structure, 1242, 130733.
Mohamed, G. A., Omar, A. M., El-Araby, M. E., Mass, S., and Ibrahim, S. R. (2023). Assessments of alpha-amylase inhibitory potential of tagetes flavonoids through in vitro, molecular docking, and molecular dynamics simulation studies. International journal of molecular sciences, 24(12), 10195.
Kushwaha, P. P., Singh, A. K., Bansal, T., Yadav, A., Prajapati, K. S., Shuaib, M., and Kumar, S. (2021). Identification of natural inhibitors against SARS-CoV-2 drugable targets using molecular docking, molecular dynamics simulation, and MM-PBSA approach. Frontiers in cellular and infection microbiology, 11, 730288.
DOI: https://doi.org/10.17509/ajse.v6i1.89885
Refbacks
- There are currently no refbacks.
Copyright (c) 2025 Universitas Pendidikan Indonesia
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.