Design, Synthesis, Computational Studies, and Anti-Proliferative Evaluation of Novel Ethacrynic Acid Derivatives Containing Nitrogen Heterocycle, Urea, and Thiourea Moieties as Anticancer Agents
Abstract
:1. Introduction
2. Results and Discussions
2.1. Chemistry
2.2. Photophysical Properties
2.3. Biological Study
2.4. Drug-Likeness Prediction
2.5. Molecular Docking
3. Materials and Methods
3.1. General Procedures
3.2. Optical Spectroscopy
3.3. Synthesis and Characterisation
3.3.1. Preparation of Intermediate compounds
3.3.2. General Experimental Procedure for the Synthesis of Products (1–10), 16(a–c), 17b, 18, and 23
3.4. Biological Evaluation
Cell Culture and Proliferation Assay
3.5. Molecular Modelling
3.5.1. Drug-Likeness
3.5.2. Molecular Docking
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Ali, R.; Mirza, Z.; Ashraf, G.M.D.; Kamal, M.A.; Ansari, S.A.; Damanhouri, G.A.; Abuzenadah, A.M.; Chaudhary, A.G.; Sheikh, I.A. New anticancer agents: Recent developments in tumor therapy. Anticancer Res. 2012, 32, 2999–3005. [Google Scholar]
- Eskens, F.A.L.M.; Verweij, J. Clinical studies in the development of new anticancer agents exhibiting growth inhibition in models: Facing the challenge of a proper study design. Crit. Rev. Oncol. Hematol. 2000, 34, 83–88. [Google Scholar] [CrossRef]
- Frangione, M.L.; Lockhart, J.H.; Morton, D.T.; Pava, L.M.; Blanck, G. Anticipating designer drug-resistant cancer cells. Drug Discov. Today 2015, 20, 790–793. [Google Scholar] [CrossRef]
- Johansson, K.; Ito, M.; Schophuizen, C.M.S.; Mathew Thengumtharayil, S.; Heuser, V.D.; Zhang, J.; Shimoji, M.; Vahter, M.; Ang, W.H.; Dyson, P.J. Characterization of new potential anticancer drugs designed to overcome glutathione transferase mediated resistance. Mol. Pharm. 2011, 8, 1698–1708. [Google Scholar] [CrossRef]
- van Iersel, M.L.P.S.; van Lipzig, M.M.H.; Rietjens, I.M.C.M.; Vervoort, J.; van Bladeren, P.J. GSTP1-1 stereospecifically catalyzes glutathione conjugation of ethacrynic acid. FEBS Lett. 1998, 441, 153–157. [Google Scholar] [CrossRef]
- Zhao, G.; Wang, X. Advance in antitumor agents targeting glutathione-s-transferase. Curr. Med. Chem. 2006, 13, 1461–1471. [Google Scholar] [CrossRef]
- O’Dwyer, P.J.; LaCreta, F.; Nash, S.; Tinsley, P.W.; Schilder, R.; Clapper, M.L.; Tew, K.D.; Panting, L.; Litwin, S.; Comis, R.L.; et al. Phase i study of thiotepa in combination with the glutathione transferase inhibitor ethacrynic acid. Cancer Res. 1991, 51, 6059–6065. [Google Scholar] [PubMed]
- Aizawa, S.; Ookawa, K.; Kudo, T.; Asano, J.; Hayakari, M.; Tsuchida, S. Characterization of cell death induced by ethacrynic acid in a human colon cancer cell line DLD-1 and suppression by N-acetyl-l-cysteine. Cancer Sci. 2003, 94, 886–893. [Google Scholar] [CrossRef] [PubMed]
- Mignani, S.; El Brahmi, N.; El Kazzouli, S.; Eloy, L.; Courilleau, D.; Caron, J.; Bousmina, M.M.; Caminade, A.-M.; Cresteil, T.; Majoral, J.-P. A novel class of ethacrynic acid derivatives as promising drug-like potent generation of anticancer agents with established mechanism of action. Eur. J. Med. Chem. 2016, 122, 656–673. [Google Scholar] [CrossRef] [PubMed]
- El Abbouchi, A.; El Brahmi, N.; Hiebel, M.-A.; Bignon, J.; Guillaumet, G.; Suzenet, F.; El Kazzouli, S. Synthesis and evaluation of a novel class of ethacrynic acid derivatives containing triazoles as potent anticancer agents. Bioorg. Chem. 2021, 115, 105293. [Google Scholar] [CrossRef] [PubMed]
- Naz, S.; Zahoor, M.; Umar, M.N.; Alghamdi, S.; Sahibzada, M.U.K.; UlBari, W. Synthesis, characterization, and pharmacological evaluation of thiourea derivatives. Open Chem. 2020, 18, 764–777. [Google Scholar] [CrossRef]
- Goffin, E.; Lamoral-Theys, D.; Tajeddine, N.; De Tullio, P.; Mondin, L.; Lefranc, F.; Gailly, P.; Rogister, B.; Kiss, R.; Pirotte, B. N-Aryl-N′-(Chroman-4-Yl) ureas and thioureas display in vitro anticancer activity and selectivity on apoptosis-resistant glioblastoma cells: Screening, synthesis of simplified derivatives, and structure–activity relationship analysis. Eur. J. Med. Chem. 2012, 54, 834–844. [Google Scholar] [CrossRef]
- Vega-Pérez, J.M.; Periñán, I.; Argandoña, M.; Vega-Holm, M.; Palo-Nieto, C.; Burgos-Morón, E.; López-Lázaro, M.; Vargas, C.; Nieto, J.J.; Iglesias-Guerra, F. Isoprenyl-thiourea and urea derivatives as new farnesyl diphosphate analogues: Synthesis and in vitro antimicrobial and cytotoxic activities. Eur. J. Med. Chem. 2012, 58, 591–612. [Google Scholar] [CrossRef]
- Ronchetti, R.; Moroni, G.; Carotti, A.; Gioiello, A.; Camaioni, E. Recent Advances in Urea- and Thiourea-Containing Compounds: Focus on Innovative Approaches in Medicinal Chemistry and Organic Synthesis. RSC Med. Chem. 2021, 12, 1046–1064. [Google Scholar] [CrossRef]
- Ghorab, M.M.; Alsaid, M.S.; El-Gaby, M.S.A.; Elaasser, M.M.; Nissan, Y.M. Antimicrobial and Anticancer Activity of Some Novel Fluorinated Thiourea Derivatives Carrying Sulfonamide Moieties: Synthesis, Biological Evaluation and Molecular Docking. Chem. Cent. J. 2017, 11, 32. [Google Scholar] [CrossRef]
- El Abbouchi, A.; El Brahmi, N.; Hiebel, M.-A.; Ghammaz, H.; El Fahime, E.; Bignon, J.; Guillaumet, G.; Suzenet, F.; El Kazzouli, S. Improvement of the chemical reactivity of michael acceptor of ethacrynic acid correlates with antiproliferative activities. Molecules 2023, 28, 910. [Google Scholar] [CrossRef]
- Bourzikat, O.; El Abbouchi, A.; Ghammaz, H.; El Brahmi, N.; El Fahime, E.; Paris, A.; Daniellou, R.; Suzenet, F.; Guillaumet, G.; El Kazzouli, S. Synthesis, anticancer activities and molecular docking studies of a novel class of 2-phenyl-5, 6, 7, 8-tetrahydroimidazo [1, 2-b] pyridazine derivatives bearing sulfonamides. Molecules 2022, 27, 5238. [Google Scholar] [CrossRef] [PubMed]
- El Abbouchi, A.; El Brahmi, N.; Hiebel, M.-A.; Bignon, J.; Guillaumet, G.; Suzenet, F.; El Kazzouli, S. Synthesis and biological evaluation of ethacrynic acid derivatives bearing sulfonamides as potent anti-cancer agents. Bioorganic Med. Chem. Lett. 2020, 30, 127426. [Google Scholar] [CrossRef]
- Idir, A.; Bouchmaa, N.; El Abbouchi, A.; El Brahmi, N.; Mrid, R.B.; Bouargalne, Y.; Mouse, H.A.; Nhiri, M.; Bousmina, M.; El Kazzouli, S. In Vitro cytotoxic, antioxidant, hemolytic and cytoprotective potential of promising ethacrynic acid derivatives. Mor. J. Chem. 2023, 11, 579–896. [Google Scholar] [CrossRef]
- Sirbu, A.D.; Diharce, J.; Martinic, I.; Chopin, N.; Eliseeva, S.V.; Guillaumet, G.; Petoud, S.; Bonnet, P.; Suzenet, F. An Original class of small sized molecules as versatile fluorescent probes for cellular imaging. Chem. Commun. 2019, 55, 7776–7779. [Google Scholar] [CrossRef] [PubMed]
- Sirbu, D.; Chopin, N.; Martinić, I.; Ndiaye, M.; Eliseeva, S.V.; Hiebel, M.-A.; Petoud, S.; Suzenet, F. Pyridazino-1, 3a, 6a-triazapentalenes as versatile fluorescent probes: Impact of their post-functionalization and application for cellular imaging. Int. J. Mol. Sci. 2021, 22, 6645. [Google Scholar] [CrossRef]
- Brouwer, A.M. Standards for photoluminescence quantum yield measurements in solution (IUPAC Technical Report). Pure Appl. Chem. 2011, 83, 2213–2228. [Google Scholar] [CrossRef]
- Hannah, R.; Beck, M.; Moravec, R.; Riss, T. CellTiter-GloTM luminescent cell viability assay: A sensitive and rapid method for determining cell viability. Promega Cell Notes 2001, 2, 11–13. [Google Scholar]
- Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 1997, 23, 3–25. [Google Scholar] [CrossRef]
- Veber, D.F.; Johnson, S.R.; Cheng, H.-Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 2002, 45, 2615–2623. [Google Scholar] [CrossRef]
- Egan, W.J.; Merz, K.M.; Baldwin, J.J. Prediction of Drug Absorption Using Multivariate Statistics. J. Med. Chem. 2000, 43, 3867–3877. [Google Scholar] [CrossRef] [PubMed]
- Daina, A.; Michielin, O.; Zoete, V. SwissADME: A Free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017, 7, 42717. [Google Scholar] [CrossRef] [PubMed]
- Haloui, R.; Daoui, O.; Mkhayar, K.; El Yaqoubi, M.; Elkhattabi, S.; Haoudi, A.; Rodi, Y.K.; Ouazzani, F.C.; Chtita, S. 3D-QSAR, Drug-Likeness, ADMET Prediction, and molecular docking studies in silico of novel 5-oxo-1-thioxo-4, 5-dihydro-1H-thiazolo [3, 4-a] quinazoline derivatives as MALT1 protease inhibitors for the treatment of B cell lymphoma. Chem. Pap. 2023, 77, 2255–2274. [Google Scholar] [CrossRef]
- Mkhayar, K.; Daoui, O.; Haloui, R.; Elkhattabi, K.; Elabbouchi, A.; Chtita, S.; Samadi, A.; Elkhattabi, S. Ligand-based design of novel quinoline derivatives as potential anticancer agents: An in-silico virtual screening approach. Molecules 2024, 29, 426. [Google Scholar] [CrossRef] [PubMed]
- Mistry, S.N.; Baker, J.G.; Fischer, P.M.; Hill, S.J.; Gardiner, S.M.; Kellam, B. Synthesis and in vitro and in vivo characterization of highly Β1-selective β-adrenoceptor partial agonists. J. Med. Chem. 2013, 56, 3852–3865. [Google Scholar] [CrossRef] [PubMed]
- Ma, X.; Liu, L.; Duan, W.; Shi, X.; Li, F.; Hua, Z. Synthesis and antifungal activity of camphoric acid-based thiourea derivatives. Chem. Ind. For. Prod. 2015, 35, 69–77. [Google Scholar] [CrossRef]
- Li, S.; Li, G.; Yang, X.; Meng, Q.; Yuan, S.; He, Y.; Sun, D. Design, synthesis and biological evaluation of artemisinin derivatives containing fluorine atoms as anticancer agents. Bioorganic Med. Chem. Lett. 2018, 28, 2275–2278. [Google Scholar] [CrossRef] [PubMed]
- «RCSB PDB: Homepage». Available online: https://www.rcsb.org/ (accessed on 9 May 2023).
- mgl-admin, «Downloads», AutoDock Vina. Available online: https://vina.scripps.edu/downloads/ (accessed on 10 May 2023).
- «Free Download: BIOVIA Discovery Studio Visualizer—Dassault Systèmes». Available online: https://discover.3ds.com/discovery-studio-visualizer-download (accessed on 10 May 2023).
Compounds | 22 | 24 |
---|---|---|
λex a (nm) | 416 | 380 |
λem b (nm) | 481 | 470 |
εmax c | 8347 | 2678 |
δ d | 63 | 128 |
ϕ e | 0.43 | 0.93 |
Brightness | 3584 | 2513 |
Colour |
Compounds | 1 | 2 | 3 | 10 | 16a | 16b | 16c | 17b | 24 |
---|---|---|---|---|---|---|---|---|---|
IC50 HL60 (µM) | 1.82 | 1.53 | 1.05 | 1.64 | 2.37 | 0.86 | 3.36 | 6.43 | 1.33 |
Compounds | Log P | HBD | HBA | NROTB | S. Has | MW | ABS | TPSA | Lipinski’s Violations |
---|---|---|---|---|---|---|---|---|---|
≤5 | <5 | <10 | - | 1 < SA < 10 | <500 | - | - | ||
EA | 2.55 | 1 | 4 | 6 | 2.43 | 303.14 | High | 63.6 | 0 |
1 | 2.71 | 2 | 4 | 8 | 2.81 | 418.27 | High | 84.08 | 0 |
2 | 2.93 | 2 | 3 | 8 | 2.8 | 417.29 | High | 71.19 | 0 |
3 | 2.79 | 1 | 4 | 8 | 2.88 | 432.30 | High | 73.22 | 0 |
4 | 3.14 | 1 | 3 | 8 | 2.89 | 431.31 | High | 60.33 | 0 |
5 | 2.93 | 1 | 4 | 8 | 2.9 | 432.3 | High | 73.22 | 0 |
6 | 3.66 | 0 | 4 | 7 | 2.92 | 403.26 | High | 61.19 | 0 |
7 | 2.48 | 1 | 5 | 8 | 3.00 | 461.29 | High | 92.78 | 0 |
8 | 2.56 | 1 | 4 | 8 | 2.70 | 379.24 | High | 68.29 | 0 |
9 | 2.15 | 1 | 4 | 8 | 2.70 | 379.24 | High | 68.29 | 0 |
10 | 2.15 | 1 | 4 | 8 | 2.61 | 379.24 | High | 68.29 | 0 |
16a | 3.15 | 3 | 4 | 13 | 3.34 | 478.37 | High | 96.53 | 0 |
16b | 3.32 | 3 | 5 | 13 | 3.22 | 482.33 | High | 96.53 | 0 |
16c | 2.63 | 3 | 5 | 14 | 3.93 | 494.37 | High | 105.76 | 0 |
17b | 3.30 | 3 | 4 | 13 | 3.26 | 498.4 | High | 111.55 | 0 |
18 | 3.33 | 1 | 5 | 10 | 3.38 | 508.37 | High | 78.95 | 1 |
Compounds | Lipinski | Veber | Egan | Bioavailability Score | Lipinski’s Violations |
---|---|---|---|---|---|
EA | Yes | Yes | Yes | 0.55 | 0 |
1 | Yes | Yes | Yes | 0.55 | 0 |
2 | Yes | Yes | Yes | 0.55 | 0 |
3 | Yes | Yes | Yes | 0.55 | 0 |
4 | Yes | Yes | Yes | 0.55 | 0 |
5 | Yes | Yes | Yes | 0.55 | 0 |
6 | Yes | Yes | Yes | 0.55 | 0 |
7 | Yes | Yes | Yes | 0.55 | 0 |
8 | Yes | Yes | Yes | 0.55 | 0 |
9 | Yes | Yes | Yes | 0.55 | 0 |
10 | Yes | Yes | Yes | 0.55 | 0 |
16a | Yes | No | Yes | 0.55 | 0 |
16b | Yes | No | Yes | 0.55 | 0 |
16c | Yes | No | Yes | 0.55 | 0 |
17b | Yes | No | Yes | 0.55 | 0 |
18 | Yes | No | Yes | 0.55 | 1 |
Compounds | Caspase-3 | ||
---|---|---|---|
EA | Hydrogen bond interactions | Hydrophobic interactions | Bond energies (kcal\mol) |
Conventional H-bond: His A278, Ser A36, Asn A35 | Alkyl and π-alkyl: Lys A38 | −5.7 | |
2 | Carbon hydrogen bond: His A121 | π–π stacked: Phe A256 | −7.4 |
3 | Conventional H-bond: Ser A251 | Alkyl and π-alkyl: Phe A250, Tyr A204 π–π stacked: Phe A256, Phe A252 | −7.3 |
Compounds | Human Glutathione S-Transferase P1-1 | ||
---|---|---|---|
EA | Hydrogen bond interactions | Hydrophobic interactions | Bond energies (kcal\mol) |
Conventional H-bond: Asn A110 | π-sigma: Tyr A118 π-alkyl: Lys A102 Halogen: Gly A114 | −6.2 | |
2 | Carbon hydrogen bond: Ile A143 Conventional H-bond: Gln A135 | π-alkyl: Val A144, Leu B48 π–π stacked: Phe B8 π sigma: LeuA88 | −6.7 |
3 | Conventional H-bond: Gln A135 | π-alkyl: Pro B128, Lys B127 | −7.00 |
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El Abbouchi, A.; Mkhayar, K.; Elkhattabi, S.; El Brahmi, N.; Hiebel, M.-A.; Bignon, J.; Guillaumet, G.; Suzenet, F.; El Kazzouli, S. Design, Synthesis, Computational Studies, and Anti-Proliferative Evaluation of Novel Ethacrynic Acid Derivatives Containing Nitrogen Heterocycle, Urea, and Thiourea Moieties as Anticancer Agents. Molecules 2024, 29, 1437. https://doi.org/10.3390/molecules29071437
El Abbouchi A, Mkhayar K, Elkhattabi S, El Brahmi N, Hiebel M-A, Bignon J, Guillaumet G, Suzenet F, El Kazzouli S. Design, Synthesis, Computational Studies, and Anti-Proliferative Evaluation of Novel Ethacrynic Acid Derivatives Containing Nitrogen Heterocycle, Urea, and Thiourea Moieties as Anticancer Agents. Molecules. 2024; 29(7):1437. https://doi.org/10.3390/molecules29071437
Chicago/Turabian StyleEl Abbouchi, Abdelmoula, Khaoula Mkhayar, Souad Elkhattabi, Nabil El Brahmi, Marie-Aude Hiebel, Jérôme Bignon, Gérald Guillaumet, Franck Suzenet, and Saïd El Kazzouli. 2024. "Design, Synthesis, Computational Studies, and Anti-Proliferative Evaluation of Novel Ethacrynic Acid Derivatives Containing Nitrogen Heterocycle, Urea, and Thiourea Moieties as Anticancer Agents" Molecules 29, no. 7: 1437. https://doi.org/10.3390/molecules29071437