Synthesis, Thermal, DFT Calculations, HOMO-LUMO, MEP, and Molecular Docking Analysis of New Derivatives of Imidazolin-4-Ones

Khedidja Merdja(1), Choukry Kamel Bendeddouche(2), Mokhtaria Drissi(3), Farah Chafika Kaouche(4), Nassima Medjahed(5), José Manuel Padrón(6), Mansour Debdab(7*), Mustapha Rahmouni(8), El Habib Belarbi(9)

(1) Laboratory of Applied Organic Synthesis, Faculty of Exact and Applied Sciences, University Oran1 Ahmed Ben Bella, El M’Naouer, Oran 31000, Algeria; Laboratory of Synthesis and Catalysis (LSCT), Faculty of Materials Sciences, University Ibn Khaldoun-Tiaret, Tiaret 14000, Algeria
(2) Laboratory of Applied Organic Synthesis, Faculty of Exact and Applied Sciences, University Oran1 Ahmed Ben Bella, El M’Naouer, Oran 31000, Algeria
(3) Laboratory of Synthesis and Catalysis (LSCT), Faculty of Materials Sciences, University Ibn Khaldoun-Tiaret, Tiaret 14000, Algeria
(4) Laboratory of Synthesis and Catalysis (LSCT), Faculty of Materials Sciences, University Ibn Khaldoun-Tiaret, Tiaret 14000, Algeria
(5) Laboratoire de Catalyse et Synthèse en Chimie Organique, Faculté des Sciences, Université de Tlemcen, Tlemcen 13000, Algeria; Faculté des Sciences et de la Technologie, Université d’Ain Témouchent, Ain Témouchent 46000, Algeria
(6) BioLab, Instituto Universitario de Bio-Organica “Antonio González”, Universidad de La Laguna, La Laguna 38200, Spain
(7) Laboratory of Synthesis and Catalysis (LSCT), Faculty of Materials Sciences, University Ibn Khaldoun-Tiaret, Tiaret 14000, Algeria
(8) Laboratory of Synthesis and Catalysis (LSCT), Faculty of Materials Sciences, University Ibn Khaldoun-Tiaret, Tiaret 14000, Algeria
(9) Laboratory of Synthesis and Catalysis (LSCT), Faculty of Materials Sciences, University Ibn Khaldoun-Tiaret, Tiaret 14000, Algeria
(*) Corresponding Author


This work focuses on synthesizing new imidazolin-4-one derivatives (2a-c), akin to leucettamine B analogs, via microwave-assisted transamination reactions. This reaction was carried out between 3-alkyl-5-dimethylamino-2-thioxo-imidazolidin-4-one (1a-c) and aniline. The structural integrity of the synthesized compounds was confirmed using NMR and MS spectroscopy, and their configurations were validated through DFT calculations. Analyses encompassed molecular electrostatic potential, frontier molecular orbitals, HOMO-LUMO energies, energy band gap, and global chemical reactivity descriptors, providing comprehensive insights into their characteristics. The investigation extended to the biological domain, employing substance activity spectra prediction (PASS) and molecular docking with Autodock Vina4 program. Notably, this holistic assessment aimed to gauge the potential regulatory effect of the compounds on cholesterol. This integrated approach contributes to compound design understanding and potential applications, spanning drug design and broader biomedical contexts.


DFT calculations; imidazolin-4-ones derivatives; HOMO-LUMO energies; microwave irradiation; molecular docking


[1] Banerjee, P., Mandhare, A., and Bagalkote, V., 2022, Marine natural products as source of new drugs: An updated patent review (July 2018-July 2021), Expert Opin. Ther. Pat., 32 (3), 317–363.

[2] Debdab, M., Carreaux, F., Renault, S., Soundararajan, M., Fedorov, O., Filippakopoulos, P., Lozach, O., Babault, L., Tahtouh, T., Baratte, B., Ogawa, Y., Hagiwara, M., Eisenreich, A., Rauch, U., Knapp, S., Meijer, L., and Bazureau, J.P., 2011, Leucettines, a class of potent inhibitors of cdc2-like kinases and dual specificity, tyrosine phosphorylation regulated kinases derived from the marine sponge leucettamine B: Modulation of alternative pre-RNA splicing, J. Med. Chem., 54 (12), 4172–4186.

[3] Najmi, A., Javed, S.A., Al Bratty, M., and Alhazmi, H.A., 2022, Modern approaches in the discovery and development of plant-based natural products and their analogues as potential therapeutic agents, Molecules, 27 (2), 349.

[4] Sengupta, S., Pabbaraja, S., and Mehta, G. 2023., C–H modification of natural products: A minimalist enabling tactic for drug discovery, API processing and bioconjugation, Chem. Commun., 59 (62), 9445–9456.

[5] Nicolaou, K.C., and Rigol, S., 2020, Perspectives from nearly five decades of total synthesis of natural products and their analogues for biology and medicine, Nat. Prod. Rep., 37 (11), 1404–1435.

[6] Debdab, M., Renault, S., Lozach, O., Meijer, L., Paquin, L., Carreaux, F., and Bazureau, J.P., 2010, Synthesis and preliminary biological evaluation of new derivatives of the marine alkaloid leucettamine B as kinase inhibitors, Eur. J. Med. Chem., 45 (2), 805–810.

[7] Keel, K.L., and Tepe, J.J., 2020, The preparation of (4H)-imidazol-4-ones and their application in the total synthesis of natural products, Org. Chem. Front., 7 (20), 3284–3311.

[8] Cho, S., Kim, S.H., and Shin, D., 2019, Recent applications of hydantoin and thiohydantoin in medicinal chemistry, Eur. J. Med. Chem., 164, 517–545.

[9] de Carvalho, P.G.C., Ribeiro, J.M., Garbin, R.P.B., Nakazato, G., Yamada Ogatta, S.F., de Fátima, Â., de Lima Ferreira Bispo, M., and Macedo, F., 2020, Synthesis and antimicrobial activity of thiohydantoins obtained from L-amino acids, Lett. Drug Des. Discovery, 17 (1), 94–102.

[10] Li, Y., Zhang, T., Ma, H., Xu, L., Zhang, Q., He, L., Jiang, J., Zhang, Z., Zhao, Z., Wang, M., and Wang, M., 2023, Design, synthesis, and antifungal/antioomycete activity of thiohydantoin analogues containing spirocyclic butenolide, J. Agric. Food Chem., 71 (16), 6249–6267.

[11] Elhady, H.A., Mohammed, S.M., Al-Shareef, H.F., and El-Mekawy, R.E., 2019, Synthesis, reactions, and applications of 2-thiohydantoin derivatives, Acta Pol. Pharm., 76 (6), 971–986.

[12] Hsu, M.H., Hsieh, C.Y., Kapoor, M., Chang, J.H., Chu, H.L., Cheng, T.M., Hsu, K.C., Lin, T.E., Tsai, F.Y., and Horng, J.C., 2020, Leucettamine B analogs and their carborane derivative as potential anti-cancer agents: Design, synthesis, and biological evaluation, Bioorg. Chem., 98, 103729.

[13] Khodair, A.I., El-Barbary, A.A., Imam, D.R., Kheder, N.A., Elmalki, F., and Ben Hadda, T., 2021, Synthesis, antiviral, DFT and molecular docking studies of some novel 1,2,4-triazine nucleosides as potential bioactive compounds, Carbohydr. Res., 500, 108246.

[14] Bendeddouche, C.K., Adjdir, M., and Benhaoua, H., 2016, Stereoselective cyclopropanation under solvent free conditions: Catalyzed by a green and efficient recyclable Cu-exchanged bentonite, Lett. Org. Chem., 13 (3), 217–223.

[15] Bendeddouche, S., Bendeddouche, C.K., and Benhaoua, H., 2021, A Convenient stereoselective method for synthesis of β-lactams under microwave irradiation with [BmIm] OH as a reusable ionic liquid, Lett. Org. Chem., 18 (12), 929–935.

[16] Chérouvrier, J.R., Carreaux, F., and Bazureau, J.P., 2002, A practical and eco-friendly synthesis of stereo controlled alkylaminomethylidene derivatives of 2-thiohydantoins by dimethylamine substitution, Tetrahedron Lett., 43 (48), 8745–8749.

[17] Kourat, O., Djafri, A., Benhalima, N., Megrouss, Y., Belkafouf, N.E.H., Rahmani, R., Daran, J.C., Djafri, A., and Chouaih, A., 2020, Synthesis, crystal structure, Hirshfeld surface analysis, spectral characterization, reduced density gradient and nonlinear optical investigation on (E)-N'-(4-nitrobenzylidene)-2-(quinolin-8-yloxy) acetohydrazide monohydrate: A combined experimental and DFT approach, J. Mol. Struct., 1222, 128952.

[18] Metwally, M.A., and Abdel-Latif, E., 2012, Thiohydantoins: Synthetic strategies and chemical reactions, J. Sulfur Chem., 33 (2), 229–257.

[19] Osyanin, V.A., Korzhenko, K.S., Rashchepkina, D.A., Osipov, D.V., and Klimochkin, Y.N., 2021, Nucleophilic vinylic substitution in perfluoroacylchromenes. Diastereoselective synthesis of push–pull enamino ketones, Russ. J. Org. Chem., 57 (7), 1053–1062.

[20] Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Mennucci, B., Petersson, G.A., Nakatsuji, H., Caricato, M., Li, X., Hratchian, H.P., Izmaylov, A.F., Bloino, J., Zheng, G., Sonnenberg, J.L., Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Vreven, T., Montgomery, Jr., J.A., Peralta, J.E., Ogliaro, F., Bearpark, M., Heyd, J.J., Brothers, E., Kudin, K.N., Staroverov, V.N., Kobayashi, R., Normand, J., Raghavachari, K., Rendell, A., Burant, J.C., Iyengar, S.S., Tomasi, J., Cossi, M., Rega, N., Millam, J.M., Klene, M., Knox, J.E., Cross, J.B., Bakken, V., Adamo, C., Jaramillo, J., Gomperts, R., Stratmann, R.E., Yazyev, O., Austin, A.J., Cammi, R., Pomelli, C., Ochterski, J.W., Martin, R.L., Morokuma, K., Zakrzewski, V.G., Voth, G.A., Salvador, P., Dannenberg, J.J., Dapprich, S., Daniels, A.D., Farkas, O., Foresman, J.B., Ortiz, J.V., Cioslowski, J., and Fox, D.J., 2009, Gaussian 09, Revision A.02, Gaussian, Inc., Wallingford CT.

[21] Dennington, R., Keith, T.A., and Millam, J.M., 2009, GaussView, Version 5, Semichem Inc., Shawnee Mission, KS.

[22] Raczyńska, E.D., Gal, J.F., Maria, P.C., Sakhawat, G.S., Fahim, M.Q., and Saeidian, H., 2022, Nitriles with high gas-phase basicity—Part II Transmission of the push–pull effect through methylenecyclopropene and cyclopropenimine scaffolds intercalated between different electron donor(s) and the cyano N-protonation site, Molecules, 27 (14), 4370.

[23] Eberhardt, J., Santos-Martins, D., Tillack, A Forli, S., 2021, AutoDock Vina 1.2.0: New docking methods, expanded force field, and python bindings, J. Chem. Inf. Model., 61 (8), 3891–3898.

[24] Boukabcha, N., Direm, A., Drissi, M., Megrouss, Y., Khelloul, N., Dege, N., Tuna, M., and Chouaih, A., 2021, Synthesis, structural determination, Hirshfeld surface analysis, 3D energy frameworks, electronic and (static, dynamic) NLO properties of o-Nitroacetanilide (o-NAA): A combined experimental and quantum chemical study, Inorg. Chem. Commun., 133, 108884.

[25] Mollaamin, F., and Monajjemi, M., 2023, Molecular modelling framework of metal-organic clusters for conserving surfaces: Langmuir sorption through the TD-DFT/ONIOM approach, Mol. Simul., 49 (4), 365–376.

[26] Suresh, C.H., Remya, G.S., and Anjalikrishna, P.K., 2022, Molecular electrostatic potential analysis: A powerful tool to interpret and predict chemical reactivity, WIREs Comput. Mol. Sci., 12 (5), e1601.

[27] Nehra, N., Tittal, R.K., and Ghule, V.D., 2021, 1,2,3-Triazoles of 8-hydroxyquinoline and HBT: Synthesis and studies (DNA binding, antimicrobial, molecular docking, ADME, and DFT), ACS Omega, 6 (41), 27089–27100.

[28] Singh, J.S., Khan, M.S., and Uddin, S., 2023, A DFT study of vibrational spectra of 5-chlorouracil with molecular structure, HOMO–LUMO, MEPs/ESPs and thermodynamic properties, Polym. Bull., 80 (3), 3055–3083.

[29] Li, D.D., and Greenfield, M.L., 2014, Chemical compositions of improved model asphalt systems for molecular simulations, Fuel, 115, 347–356.

[30] Mulliken, R.S., 1962, Criteria for the construction of good self‐consistent‐field molecular orbital wave functions, and the significance of lCAO‐MO population analysis, J. Chem. Phys., 36 (12), 3428–3439.

[31] Rigby, J., and Izgorodina, E.I., 2013, Assessment of atomic partial charge schemes for polarisation and charge transfer effects in ionic liquids, Phys. Chem. Chem. Phys., 15 (5), 1632–1646.

[32] Drissi, M., Benhalima, N., Megrouss, Y., Rachida, R., Chouaih, A., and Hamzaoui, F., 2015, Theoretical and experimental electrostatic potential around the m-nitrophenol molecule, Molecules, 20 (3), 4042–4054.

[33] Abraham, C.S., Prasana, J.C., Muthu, S., Rizwana B, F., and Raja, M., 2018, Quantum computational studies, spectroscopic (FT-IR, FT-Raman and UV–Vis) profiling, natural hybrid orbital and molecular docking analysis on 2,4 Dibromoaniline, J. Mol. Struct., 1160, 393–405.

[34] Guediri, A., Bouguettoucha, A., Chebli, D., Chafai, N., and Amrane, A., 2020, Molecular dynamic simulation and DFT computational studies on the adsorption performances of methylene blue in aqueous solutions by orange peel-modified phosphoric acid, J. Mol. Struct., 1202, 127290.

[35] Politzer, P., and Murray, J.S., 2021, Electrostatic potentials at the nuclei of atoms and molecules, Theor. Chem. Acc., 140 (1), 7.

[36] Filimonov, D.A., Lagunin, A.A., Gloriozova, T.A., Rudik, A.V., Druzhilovskii, D.S., Pogodin, P.V., and Poroikov, V.V., 2014, Prediction of the biological activity spectra of organic compounds using the PASS online web resource, Chem. Heterocycl. Compd., 50 (3), 444–457.


Article Metrics

Abstract views : 1518 | views : 740 | views : 265

Copyright (c) 2023 Indonesian Journal of Chemistry

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.


Indonesian Journal of Chemistry (ISSN 1411-9420 /e-ISSN 2460-1578) - Chemistry Department, Universitas Gadjah Mada, Indonesia.

Analytics View The Statistics of Indones. J. Chem.