Zahraa Ali Nashoor Alnawas (1)
General background: 1,3,4-oxadiazole derivatives are well-established heterocycles with broad pharmacological potential, and metal coordination frequently enhances their therapeutic profiles. Specific background: Recent studies highlight the need for compounds capable of dual modulation of metabolic and endocrine disorders, particularly diabetes and hyperthyroidism, where single-target therapies often yield limited outcomes. Knowledge gap: Despite promising reports, few studies have integrated experimental pharmacology with quantum chemical modeling to explain how metal coordination influences biological potency. Aims: This research synthesized a new oxadiazole–indolinone ligand and its Co(II), Ni(II), Cr(III), and Fe(III) complexes and evaluated their antidiabetic and anti-hyperthyroid activities through in vivo assays supported by DFT calculations and molecular docking. Results: All complexes demonstrated dose-dependent activity, with Co(II) exhibiting the strongest glucose reduction (120 ± 7 mg/dL) and T₄ suppression (7.1 ± 0.4 µg/dL), consistent with superior docking affinities and favorable electronic descriptors. Novelty: This study correlates spectroscopic, computational, docking, and pharmacological findings in a unified structure–activity interpretation. Implications: The results indicate that metal coordination significantly boosts biological efficacy, positioning Co(II) complexes as strong candidates for future dual-action therapeutics in diabetes and hyperthyroidism.Highlight :
Metal complexation improves biological effectiveness of the ligand.
Co(II) complex shows the strongest dual activity based on results.
Docking findings align with experimental data, supporting the SAR.
Keywords : 1,3,4-Oxadiazole, Transition Metal Complexes, DFT, Molecular Docking, Antidiabetic and Anti-Hyperthyroid Activity
Salahuddin, A. Mazumder, M. S. Yar, R. Mazumder, G. S. Chakraborthy, M. J. Ahsan, and M. U. Rahman, Updates on Synthesis and Biological Activities of 1,3,4-Oxadiazole: A Review, Synthetic Communications, vol. 47, no. 13, pp. 1805–1847, 2017.
S. Bajaj, V. Asati, J. Singh, and P. P. Roy, 1,3,4-Oxadiazoles: An Emerging Scaffold to Target Growth Factors, Enzymes and Kinases as Anticancer Agents, European Journal of Medicinal Chemistry, vol. 97, pp. 124–141, 2015.
S. Bala, V. Saini, S. Kamboj, and D. N. Prasad, Exploring Anti-inflammatory Potential of 1,3,4-Oxadiazole Derivatives as Promising Lead, International Journal of Pharmaceutical Sciences Review and Research, vol. 17, pp. 84–89, 2012.
H. J. Khalilullah, M. Ahsan, M. Hedaitullah, S. Khan, and B. Ahmed, 1,3,4-Oxadiazole: A Biologically Active Scaffold, Mini-Reviews in Medicinal Chemistry, vol. 12, pp. 789–801, 2012, doi: 10.2174/138955712801264800.
S. Bajaj, P. P. Roy, and J. Singh, 1,3,4-Oxadiazoles as Telomerase Inhibitor: Potential Anticancer Agents, Anti-Cancer Agents in Medicinal Chemistry, vol. 17, pp. 1869–1883, 2018.
K. Kumar, P. Jayaroopa, and G. Vasanth Kumar, Comprehensive Review on the Chemistry of 1,3,4-Oxadiazoles and Their Applications, International Journal of ChemTech Research, vol. 4, no. 4, pp. 1782–1791, 2012.
D. A. Najeeb, Synthesis of Heterocyclic Compounds, Journal of Al-Nahrain University, vol. 14, no. 3, pp. 1–6, 2011.
K. Kishore et al., Synthesis and Evaluation of Oxadiazole Compounds, European Journal of Medicinal Chemistry, vol. 45, no. 11, pp. 2010–2015, 2010.
S. M. Merdasa, Synthesis, Characterization, Biological Activity and Quantum Chemical Calculations of New Oxadiazole Derivatives, Journal of Thi-Qar Sciences, vol. 65, no. 5, pp. 635–645, 2022.
S. Menati, H. Amiri, and M. Riahi, Synthesis and Biological Activities of Transition Metal Complexes, Comptes Rendus Chimie, vol. 18, no. 11–12, pp. 1154–1162, 2015.
E. Kraka and D. Cremer, Computer Design of Anticancer Drugs: A New Enediyne Warhead, Journal of the American Chemical Society, vol. 122, no. 34, pp. 8245–8264, 2000.
W. Saaed et al., Catalyst- and Organic Solvent-Free Synthesis, Structural and Theoretical Studies of 1-Arylidenamino-2,4-Disubstituted-2-Imidazoline-5-Ones, Results in Chemistry, vol. 2, pp. 1–8, 2020.
S. S. Affat, M. Y. Hayal, and I. A. Flifel, Synthesis and Characterization of a New Ligand (3-Hydrazino-N-Isopropylidene-5-Methyl-4H-1,2,4-Triazole-4-Amine) and its Complexes With Fe(III), Co(III), and Ni(II), Journal of Thi-Qar Science, vol. 5, no. 4, pp. 1–7, 2016.
A. K. Ajeel, I. A. Flifel, and A. N. Al-Jabery, Synthesis, Characterization and Antibacterial Study of New 2-Ethyl-5-[(3-Phenyl-5-Sulfanyl-4H-1,2,4-Triazol-4-yl)Imino]-Methylbenzene-1,4-Diol and Their Transition Metal Complexes, University of Thi-Qar Journal, vol. 12, no. 4, pp. 1–7, 2017.
S. Alghool, W. Al Zoubi, and A. El-Azzouny, Synthesis, Characterization and Biological Evaluation of Some Transition Metal Complexes With Schiff Base Ligands, Journal of Molecular Structure, vol. 1250, p. 131792, 2022.
T. Ghosh, R. Saha, and A. Patra, Transition Metal Complexes of Bioactive Ligands: Structural Aspects and Therapeutic Potential, Coordination Chemistry Reviews, vol. 442, p. 213924, 2021.
B. Niu, H. Li, and Y. Zhang, Chromium(III) Complexes as Insulin-Mimetic Agents: Mechanistic Insights and Biological Implications, Inorganica Chimica Acta, vol. 511, p. 119847, 2020.
M. M. Rahman, M. A. Alam, and M. Lee, Metal-Based Inhibitors of Alpha-Glucosidase and Their Therapeutic Applications in Diabetes Management, European Journal of Medicinal Chemistry, vol. 174, pp. 231–243, 2019.
S. Kumar and P. Kaur, Quantum Chemical Studies of Transition Metal Complexes: Frontier Orbital Analysis and Bioactivity Correlation, Journal of Molecular Graphics and Modelling, vol. 108, p. 107980, 2021.
R. Singh, R. Pandey, and P. Gupta, Molecular Docking and Pharmacological Evaluation of Schiff Base Metal Complexes as Antidiabetic and Antithyroid Agents, Bioorganic Chemistry, vol. 121, p. 105691, 2022.
Y. Zhao and D. G. Truhlar, The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements, Theoretical Chemistry Accounts, vol. 120, pp. 215–241, 2008.
O. Trott and A. J. Olson, AutoDock Vina: Improving the Speed and Accuracy of Docking With a New Scoring Function, Efficient Optimization and Multithreading, Journal of Computational Chemistry, vol. 31, no. 2, pp. 455–461, 2010.
G. A. Brent, Mechanisms of Thyroid Hormone Action, Journal of Clinical Investigation, vol. 122, no. 9, pp. 3035–3043, 2012.