SYNTHESIS, CHARACTERIZATION, AND IN SILICO STUDIES OF TRICARBONYL[Η⁴-5-(N-(4-HYDROXYPHENYL) CINNAMAMIDE) CYCLOHEXA-1,3-DIENE] IRON AND ITS DEMETALLATED DERIVATIVE AS POTENTIAL ANTILEISHMANIAL AGENTS

Authors

Keywords:

Leishmaniasis, Acetaminophen-based Chalcone, Tricarbonyl (ƞ5-cyclohexadienyl) Iron hexafluorophosphate, Demetallation, Silico Studies

Abstract

Leishmaniasis is a neglected tropical disease caused by a protozoan species of the genus Leishmania. The treatment of leishmaniasis has remained insufficient due the limitations of existing drugs.  This has necessitated the need to search for new drugs. Acetaminophen-based chalcone N-(4-hydroxylphenylcinnamamide (ACCH)  of tricarbonyl (ƞ5-cyclohexadienyl) Iron hexafluorophosphate have been synthesized according to a published procedure to give tricarbonyl [ƞ4-5(N-(4-hydroxylphenyl) cinnamamide) cyclohexa-1,3-diene) Iron (ADDUCT) which on removal of the tricarbonyl moiety through demetallation gave (E)-3-(1ʹ,2ʹ-dihydro-[1ʹ,1ʹ-biphenyl]-3-yl)-N-(4-hydroxyphenyl)acrylamide) (DEM). The synthesized compounds were characterized using Infra-red measurement. The In-silico studies of ACCH, ADDUCT and DEM were conducted against leishmanolysin (ID PDB: 1LML) using PyRx and visualized using Biovia Discovery 2024 with Miltefosine used as standard drug. The ADMET analysis of the synthesized compounds and the standard drugs was carried out using SwissADME and Protox 3.0. The Infra-red data showed the presence of ν(CO) band due to coordinated diene organometallic moiety at 2100 cm-1 and 1910 cm-1 in the ADDUCT, absent in DEM and the emergence of new Fe-C band at 495 cm-1 .  The docking results showed that ACCH, ADDUCT and DEM with docking scores values of -6.4, -7.4, and -8.1 kcal/mol  interact more with amino acids in the active sites of receptor protein via H-bond, pi-pi interaction than the standard drugs miltefosine (docking score -5.0 kcal/mol). ADMET analysis showed good oral bioavailability, less toxicity and high gastrointestinal absorption compared to Miltefosine. This can serve as a lead to potential antileishmanial drugs.

Dimensions

Adebesin T.T., Oladosu I. A., Obi-Egbedi N. O., and Odiaka T. I. (2016). Demetallation, antimicrobial and computational studies of methoxy-1, 3-diene substituted products from addition of natural products to tricarbonyl (2-methoxycyclo hexadienyl) iron tetrafluoroborate. Journal of Organometallic Chemistry 819, 87-94.

Adebesin, T. T., Odozi, N. W., Oladosu, I. A., and Odiaka, T. I. (2019). Antimicrobial and theoretical corrosion studies of 1, 3-diene substituted natural products of tricarbonyl (cyclohexadienyl) irontetrafluoroborate. Inorganic Chemistry Communications, 107, 107501.

Akbaria M., Oryan A., and Hatam G., (2017). Application of nanotechnology in treatment of leishmaniasis: A Review. Acta Tropica 172, 86–90.

Albini A., Peneis G., and Donatelli F. Cammarota, R., De Flora, S. and Noonan, D.M.,. (2010). Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention. Journal National Cancer Institute, 102, 14–25.

Allardyce, C. S., & Dyson, P. J. (2006). Medicinal properties of organometallic compounds. In Bioorganometallic Chemistry (pp. 177-210). Berlin, Heidelberg: Springer Berlin Heidelberg.

Ambarwati, N. S. S., Azminah, A., and Ahmad, I. (2022). Molecular docking, physicochemical and drug-likeness properties of isolated compounds from Garcinia latissima Miq. On elastase enzyme: In silico analysis. Pharmacognosy Journal, 14(2), 282-288. https://doi.org/10.5530/pj.2022.14.35

Ashburn, T.T. and Thor, K.B., (2004). Drug repositioning: identifying and developing new uses for existing drugs. Nature reviews Drug discovery, 3(8), 673-683.

Ayoub Samir S. (2021). Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action. Temperature (Austin). 8(4), 351–371.

Azubuike, P. C., Imo, U. F., Ogbonna, C. K., Akinreni, T., Udofia, M. D., Odo, O. J., and Nwadiche, M. (2025). Towards neglected tropical diseases elimination in Nigeria: addressing the stigma and mental health nexus. Discover Social Science and Health, 5(1), 19.

Braun R.U., Ansorge M., and Müller T.J.J. (2006). Coupling isomerization synthesis of chalcones. Chem European Journal, 12, 9081-9094.

Bustamante, C., Ochoa, R., Asela, C. and Muskus, C., (2019). Repurposing of known drugs for leishmaniasis treatment using bioinformatic predictions, in vitro validations and pharmacokinetic simulations. Journal of Computer-Aided Molecular Design, 33(9), 845-854.

Campos-Buzzi F., Padaratz P., Meira A. V., Corrêa R., Nunes R.J and Cechinel-Filho V., (2007). 4´-Acetamidochalcone Derivatives as Potential Antinociceptive Agents. Molecules. 12, 896-906.

Chellan, P. and Sadler, P.J., (2020). Enhancing the activity of drugs by conjugation to organometallic fragments. Chemistry–A European Journal, 26(40), 8676-8688.

Cheng, P., Yang, L., Huang, X., Wang, X. and Gong, M., (2020). Chalcone hybrids and their antimalarial activity. Archiv der Pharmazie, 353(4), 1900350.

Cornelissen F.M.G., Markert G., Deutsch G., Antonara M., Faaij N., Bartelink I., Noske D., Vandertop W.P., Bender A., and Westerman B.A. (2023). Explaining Blood−Brain Barrier Permeability of Small Molecules by Integrated Analysis of Different Transport Mechanisms. Journal of Medicinal Chemistry, 66, 7253−7267.

Cosma, C., Maia, C., Khan, N., Infantino, M and Del Riccio, M. (2024). Leishmaniasis in humans and animals: A One Health approach for surveillance, prevention and control in a changing world. Tropical Medicine and Infectious Disease, 9(11), 258.

Czeleń, P., Jeliński, T., Skotnicka, A., Szefler, B. and Szupryczyński, K., (2023). ADMET and Solubility analysis of new 5-Nitroisatine-based inhibitors of CDK2 enzymes. Biomedicines, 11(11), 3019.

De Mello, M.V.P., de Azevedo Abrahim-Vieira, B., Domingos, T.F.S., de Jesus, J.B., de Sousa, A.C.C., Rodrigues, C.R. and de Souza, A.M.T., (2018). A comprehensive review of chalcone derivatives as antileishmanial agents. European journal of medicinal chemistry, 150, 920-929.

Desai, T. H and Joshi, S. V. (2019). In silico evaluation of apoptogenic potential and toxicological profile of triterpenoids. Indian journal of pharmacology, 51(3), 181–207. https://doi.org/10.4103/ijp.IJP_90_18

de Santiago-Silva, K.M., Bortoleti, B.T.D.S., Oliveira, L.D.N., Maia, F.L.D.A., Castro, J.C., Costa, I.C., Lazarin, D.B., Wardell, J.L., Wardell, S.M., Albuquerque, M.G. and Lima, C.H.D.S., (2022). Antileishmanial activity of 4, 8-dimethoxynaphthalenyl chalcones on Leishmania amazonensis. Antibiotics, 11(10), 1402.

Domínguez-Villa F.X., Duran-Iturbide N.A., and Avila-Zarraga J.G., (2021). Synthesis, molecular docking, and in silico ADME/Tox profiling studies of new 1-aryl-5-(3-azidopropyl) indol-4-ones: potential inhibitors of SARS CoV-2 main protease, Bioorganic Chemistry, 106: 104497.

Dorlo, T.P., Rijal, S., Ostyn, B., de Vries, P.J., Singh, R., Bhattarai, N., Uranw, S., Dujardin, J.C., Boelaert, M., Beijnen, J.H. and Huitema, A.D., (2014). Failure of miltefosine in visceral leishmaniasis is associated with low drug exposure. The Journal of infectious diseases, 210(1), 146-153.

Durán-Iturbide, N. A., Díaz-Eufracio, B. I., & Medina-Franco, J. L. (2020). In silico ADME/Tox profiling of natural products: A focus on BIOFACQUIM. ACS omega, 5(26), 16076-16084.

Eugene-Osoikhia, T.T., Olawoyin, A.S., Aasegh, T.J., Odozi, N.W., Ojo, N.D., Oyetunde, T., Yeye, E.O., Akong, R.A., Onche, E.U., Oyeneyin, O.E. and Oladosu, I.A.. (2025). Facile synthesis, characterization, molecular and dynamic optical properties of metronidazole and sulfamethoxazole adducts of tricarbonyl (1-5-η-2-methoxycyclohexadienylium) iron. Discover Chemistry, 2(1), 1-21.

Gao, F., Huang, G., & Xiao, J. (2020). Chalcone hybrids as potential anticancer agents: Current development, mechanism of action, and structure‐activity relationship. Medicinal research reviews, 40(5), 2049-2084.

Garcia A.R., Oliveira D.M.P., Jesus J.B., Souza A.M.T., Sodero A.C.R., Vermelho A.B., Leal I.C.R., Souza R.O.M.A., Miranda LSM, Pinheiro A.S and Rodrigues I.A. (2021). Identification of Chalcone Derivatives as Inhibitors of Leishmania infantum Arginase and Promising Antileishmanial Agents. Frontiers in Chemistry, 8:624678.

Garcia A.R., Oliveira D.M.P., Jesus J.B., Souza A.M.T., Sodero A.C.R., Vermelho A.B., Leal I.C.R., Souza R.O.M.A., Miranda LSM, Pinheiro A.S and Rodrigues I.A. (2021). Identification of Chalcone Derivatives as Inhibitors of Leishmania infantum Arginase and Promising Antileishmanial Agents. Frontiers in Chemistry, 8, 624678.

Graham, G. G., Davies, M. J., Day, R. O., Mohamudally, A., & Scott, K. F. (2013). The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings. Inflammopharmacology, 21(3), 201-232.

Henry, E.J., Bird, S.J., Gowland, P., Collins, M. and Cassella, J.P., 2020. Ferrocenyl chalcone derivatives as possible antimicrobial agents. The Journal of antibiotics, 73(5), pp.299-308.

Khaldan A., Bouamrane S., El-mernissi R., Maghat H., Sbai A., Bouachrine M., and Lakhlifi T. (2023). Molecular Docking, ADMET Prediction, and Quantum Computational on 2-Methoxy Benzoyl Hydrazone Compounds as Potential Antileishmanial Inhibitors. Biointerface Research in Applied Chemistry, 13 (4), 302.

Korb O., Stïtzle, T., and Exner, T. E., (2009). Empirical scoring functions for advanced protein-ligand docking with plants. J Chem Inf Model, 49(1):84-96.

Kouznetsov, V. V. (2024). Exploring acetaminophen prodrugs and hybrids: a review. RSC advances, 14(14), 9691-9715.

Kudo S. and Nakashima S. (2020). Changes in IR band areas and band shifts during water adsorption to lecithin and ceramide. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 228, 117779.

Lin, Y., Zhang, M., Lu, Q., Xie, J., Wu, J. and Chen, C., (2019). A novel chalcone derivative exerts anti-inflammatory and anti-oxidant effects after acute lung injury. Aging (Albany NY), 11(18), 7805.

Lipinski, C.A., (2004). Lead- and drug-like compounds: the rule-of five revolutions. Drug Discovery Today Tech. 1, 337–341.

Loganathan M., Dinesh K. S., Prabhakar V. and Chithra A. and Muthuraj M., (2022). Synthesis, Characterization and In-Vitro Anti-Inflammatory and Anti-Oxidant Activity of Some Novel Chalcone Based Acetaminophen Derivatives. World Journal of Pharmaceutical Research. 11(15); 862-867.

Mahapatra, D. K., Bharti, S. K., & Asati, V. (2017). Chalcone derivatives: anti-inflammatory potential and molecular targets perspectives. Current topics in medicinal chemistry, 17(28), 3146-3169.

Martínez, F.; Jouyban, A.; and Acree, W.E. (2017). Pharmaceuticals Solubility is Still Nowadays Widely Studied Everywhere. Pharmaceutical Sciences, 23, 1–2.

Mohapatra, S. (2014). Drug resistance in leishmaniasis: Newer developments. Tropical parasitology, 4(1), 4-9.

Monzote L. (2009). Current Treatment of Leishmaniasis: A Review. The Open Antimicrobial Agents Journal, 1, 9-19.

Mudi S. Y., Usman M. T., and Ibrahim S., (2015). Clinical and Industrial Application of Organometallic Compounds and Complexes: A Review. American Journal of Chemistry and Applications. 2 (6), 151-158.

Odhar H.A., Hashim A.F. and Humadi S.S. (2022). Molecular docking analysis and dynamics simulation of salbutamol with the monoamine oxidase B (MAO-B) enzyme. Bioinformation 18(3): 304-309.

Odiaka T.I., Adebesin T.T., and Oladosu I.A., (2014). Demetallation of 1,3-diene products obtained from addition of natural products to tricarbonyl(cyclohexadienyl)iron tetrafluoroborate. Journal of Organometallic Chemistry, 761, 179-189.

Ojuka, P., Kimani, N. M., Apollo, S., Nyariki, J., Ramos, R. S., and Santos, C. B. R. (2023). Phytochemistry of the Vepris genus plants: A review and in silico analysis of their ADMET properties. In South African Journal of Botany, 157, 106–114). https://doi.org/10.1016/j.sajb.2023.03.057

Okeke, I., and Okeke, C. (2022). Molecular Docking and Analysis of In Silico Generated Ligands Against SARS-CoV-2 Spike and Replicase Proteins. https://doi.org/10.21203/rs.3.rs-2069911/v1

Ononamadu, C. J., & Ibrahim, A. (2021). Molecular docking and prediction of ADME/drug-likeness properties of potentially active antidiabetic compounds isolated from aqueous-methanol extracts of Gymnema sylvestre and Combretum micranthum. Biotechnologia, 102(1), 85–99. https://doi.org/10.5114/bta.2021.103765

Oryan, A., (2015). Plant-derived compounds in treatment of leishmaniasis. Iranian Journal of Veterinaty. 16, 1–19.

Rivas, F., Del Mármol, C., Scalese, G., Pérez Díaz, L., Machado, I., Blacque, O., Salazar, F., Coitiño, E.L., Benítez, D., Medeiros, A. and Comini, M., (2024). Multifunctional organometallic compounds active against infective trypanosomes: Ru (II) ferrocenyl derivatives with two different bioactive ligands. Inorganic Chemistry, 63(25), 11667-11687.

Roatt, B. M., de Oliveira Cardoso, J. M., De Brito, R. C. F., Coura-Vital, W., de Oliveira Aguiar- Soares, R. D., and Reis, A. B. (2020). Recent advances and new strategies on leishmaniasis treatment. Applied Microbiology and Biotechnology, 104:21, 8965-8977.

Rocha, S., Ribeiro, D., Fernandes, E., & Freitas, M. (2020). A systematic review on anti-diabetic properties of chalcones. Current medicinal chemistry, 27(14), 2257-2321.

Rodrigues-Junior V.S., et al., (2020). Nonclinical evaluation of IQG-607, an antituberculosis candidate with potential use in combination drug therapy. Regulatory Toxicology and Pharmacology 111: 104553.

Sahu, N.k., Balbhadra, S.S., Choudhary, J., and Kohli, D.V. (2012). Exploring pharmacological significance of chalcone scaffold: a review. Current medicinal chemistry, 19(2), 209-225.

Sinha Mousumi, Jagadeesan Rahul, Kumar Neeraj, Saha Satabdi, Kothandan Gugan and Kumar Diwakar (2020): In-silico studies on Myo inositol-1-phosphate synthase of Leishmania donovani in search of anti-leishmaniasis, Journal of Biomolecular Structure and Dynamics, 40(8), 3371-3384.

Soba M, Scalese G, Casuriaga F, Perez N, Veiga N, Echeverria GA, Piro OE, Faccio R, Perez-Diaz L, Gasser G, Machado I, and Gambino D. (2023). Multifunctional organometallic compounds for the treatment of Chagas disease: Re (i) tricarbonyl compounds with two different bioactive ligands. Dalton Transactions, 52(6), 1623-1641.

Srivastava, S., Mishra, J., Gupta, A.K., Singh, A., Shankar, P. and Singh, S., (2017). Laboratory confirmed miltefosine resistant cases of visceral leishmaniasis from India. Parasites & vectors, 10(1), p.49.

Sundar, S., Chakravarty, J., Rai, V.K., Agrawal, N., Singh, S.P., Chauhan, V. and Murray, H.W., (2007)(a). Amphotericin B treatment for Indian visceral leishmaniasis: response to 15 daily versus alternate-day infusions. Clinical Infectious Diseases, 45(5), 556-561.

Sundar, S., Jha, T.K., Thakur, C.P., Sinha, P.K. and Bhattacharya, S.K., (2007)(b). Injectable paromomycin for visceral leishmaniasis in India. New England Journal of Medicine, 356(25), 2571-2581.

Thorn C. F., Aklilluc E., Kleina T.E., and Altman R. B., (2012). PharmGKB summary: very important pharmacogene information for CYP1A2. Pharmacogenetics Genomics. 22(1): 73–77.

Tirona, R. G., and Kim, R. B. (2017). Introduction to clinical pharmacology. Clinical and Translational Sciences, 365–388.

Tran, P.; Pyo, Y.C.; Kim, D.H.; Lee, S.E.; Kim, J.K.; and Park, J.S. (2019). Overview of the Manufacturing Methods of Solid Dispersion Technology for Improving the Solubility of Poorly Water-Soluble Drugs and Application to Anticancer Drugs. Pharmaceutics, 11, 132.

Trott, O., and Olson, A. J. (2010). AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 31(2), 455–461.

Ugwu D. I., Ezema D.E., Okoro U.C., Eze F.U., Ekoh O. C., Egbujora M. C. and Ugwuja D.I., (2015). Synthesis and pharmacological applications of chalcones: A review. International Journal of Chemical Science: 13(1), 459-500.

Vilar, S.; Sobarzo-Sánchez, E.; and Uriarte, E. (2019). In Silico Prediction of P-glycoprotein Binding: Insights from Molecular Docking Studies. Current Medicinal Chemistry, 26, 1746–1760.

Waring, M. J. (2010). Lipophilicity in drug discovery. Expert opinion on drug discovery, 5(3), 235-248.

Word Health Organization (WHO). Leishmaniasis. 12 January 2023. Available online: https://www.who.int/news-room/fact-sheets/detail/leishmaniasis(accessedon11October2024)

World Health Organization, (2024). Neglected tropical diseases. Available from: https://www.who.int/news-room/questions-and-answers/item/neglected-tropical-diseases

Xu, S., Chen, M., Chen, W., Hui, J., Ji, J., Hu, S., Zhou, J., Wang, Y. and Liang, G., (2015). Chemopreventive effect of chalcone derivative, L2H17, in colon cancer development. BMC cancer, 15(1), 870.

Zanger U.M., and Schwab M., (2013). Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacology and Therapeutics 138 (1): 103–141.

Zapata, F., López-Fernández, A., Ortega-Ojeda, F., Quintanilla, G., García-Ruiz, C., and Montalvo, G. (2021). Introducing ATR-FTIR Spectroscopy through Analysis of Acetaminophen Drugs: Practical Lessons for Interdisciplinary and Progressive Learning for Undergraduate Students. Journal of Chemical Education, 98(8), 2675–2686. https://doi.org/10.1021/acs.jchemed.0c01231

2D and 3D Interaction ACCH with Leishmanolysin (ID PDB: 1LML)

Published

04-11-2025

How to Cite

Eugene-Osoikhia, T., Abiodun, R. O., & Ogwuche, S. (2025). SYNTHESIS, CHARACTERIZATION, AND IN SILICO STUDIES OF TRICARBONYL[Η⁴-5-(N-(4-HYDROXYPHENYL) CINNAMAMIDE) CYCLOHEXA-1,3-DIENE] IRON AND ITS DEMETALLATED DERIVATIVE AS POTENTIAL ANTILEISHMANIAL AGENTS. FUDMA JOURNAL OF SCIENCES, 9(11), 356 – 366. https://doi.org/10.33003/fjs-2025-0911-3670

Issue

Vol. 9 No. 11 (2025): FUDMA Journal of Sciences - Vol. 9 No. 11

Section

Research Articles
Copyright & Licensing

Copyright (c) 2025 Tunmise Eugene-Osoikhia, Racheal Oluwaseun Abiodun, Sunday Ogwuche

Creative Commons License

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

How to Cite

Eugene-Osoikhia, T., Abiodun, R. O., & Ogwuche, S. (2025). SYNTHESIS, CHARACTERIZATION, AND IN SILICO STUDIES OF TRICARBONYL[Η⁴-5-(N-(4-HYDROXYPHENYL) CINNAMAMIDE) CYCLOHEXA-1,3-DIENE] IRON AND ITS DEMETALLATED DERIVATIVE AS POTENTIAL ANTILEISHMANIAL AGENTS. FUDMA JOURNAL OF SCIENCES, 9(11), 356 – 366. https://doi.org/10.33003/fjs-2025-0911-3670