Molecular Docking, Molecular Dynamic Simulation, ADMET, Synthesis, and Preliminary Cytotoxic Activity of New Triazole-Based Derivatives with Expected Histone Deacetylase Inhibition Activity
DOI:
https://doi.org/10.31351/vol33iss(4SI)pp101-110Keywords:
: HDAC inhibitor, Vorinostat, Molecular docking, MD simulation, Antiproliferative activity.Abstract
Targeting histone deacetylase enzymes (HDACs) is an effective way to treat a variety of diseases, including cancer. A number of HDAC inhibitors (HDACi) have been clinically used. Most of the clinically used HDACi are pan-inhibitors and have poor pharmacokinetic properties. Therefore, several attempts are ongoing to develop new HDACis with optimum structural features to overcome the structural limitations. In this work, six new triazole-based compounds (k1-k6) were proposed via special modification of common pharmacophores of HDACi using 1,2,4-triazole as a zinc-binding group (ZBG), diverse group in CAP group, and hydrophobic linker. These compounds were analyzed by docking study against HDAC6, HDAC2, and HDAC8. The docking study revealed that the proposed compounds has docking score of k1 [(E)-4-((thiazol-2-ylimino)methyl)-N-(1H-1,2,4- triazol-3-yl)benzamide (-8.54 Kcal/mol)], k2 [(E)-4-((phenylimino)methyl)-N-(1H-1,2,4- triazol-3-yl)benzamide (-8.47 Kcal/mol)], k3 [(E)-4-((p-tolylimino)methyl)-N-(1H-1,2,4- triazol-3-yl)benzamide (-8.46 Kcal/mol)], k4 [(E)-4-((naphthalen-2-ylimino)methyl)-N-(1H-1,2,4- triazol-3-yl)benzamide (-8.32 Kcal/mol)], k5 [(E)-4-(((4-bromophenyl)imino)methyl)-N-(1H-1,2,4- triazol-3-yl)benzamide (-7.62 Kcal/mol)], k6 [(E)-4-(((4-methoxyphenyl)imino)methyl)-N-(1H-1,2,4- triazol-3-yl)benzamide (-6.77 Kcal/mol)], and vorinostat (-9.1 Kcal/mol) against HDAC8. The final compounds were synthesized using conventional organic synthesis methods starting from amide bond formation using the coupling reagents EDCi, DMAP, HOBt, and DIPEA, followed by a Schiff base reaction between the produced aldehyde and various amines to afford the final compounds. All reactions were monitored via TLC plates, and purified using recrystallization and/or column chromatography. The chemical structure for the intermediate and final compounds was characterized using IR and NMR spectroscopy. The preliminary MTT assay of compounds k1, k2, and k5showed a comparable antiproliferative activity with vorinostat against HeLa cells with IC50 values for compound k1 (4.9 µM), k2 (5.3 µM) and k5(5.3 µM) while IC50 for vorinostat was (8.4 µM). Most interestingly, compound k5 showed higher antiproliferative activity against A549 lung cancer cells with an IC50 value (4.4 µM) in comparison to vorinostat (9.5 µM), while compounds k1, k2, and k6 have lower cytotoxic effects with IC50 of (19.2, 17.6, and 10.6 µM) respectively.
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References
Ames BN, Gold LS, Willett WC. The causes and prevention of cancer. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5258-65. doi: 10.1073/pnas.92.12.5258. PMID: 7777494; PMCID: PMC41674.
Cheng, Y., He, C., Wang, M. et al. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Sig Transduct Target Ther 4, 62 (2019). https://doi.org/10.1038/s41392-019-0095-0
Ameer H. Alwash, Noor Hatef Naser, Synthesis, characterization, and vitro evaluation of new materials in vorinostat analogs containing biomolecules, Materials Today: Volume 60, Part 3, 2022, https://doi.org/10.1016/j.matpr.2021.11.016.
Al-Hamashi, A., Abdulhadi, S., Ali, R. (2023). 'Evaluation of Zinc Chelation Ability for Non-Hydroxamic Organic Moieties', Egyptian Journal of Chemistry, 66(5), pp. 215-221. doi: 10.21608/ejchem.2022.147377.6415
Hasan, Y., & Al-Hamashi, A. (2022). Identification of Selisistat Derivatives as SIRT1-3 Inhibitors by in Silico Virtual Screening. Koray SAYIN.
Ganai SA, Farooq Z, Banday S, Altaf M. In silico approaches for investigating the binding propensity of apigenin and luteolin against class I HDAC isoforms. Future Med Chem. 2018 Aug 1;10(16):1925-1945. doi: 10.4155/fmc-2018-0020. Epub 2018 Jul 11. PMID: 29992822.
Al-Hamashi AA, Koranne R, Dlamini S, Alqahtani A, Karaj E, Rashid MS, Knoff JR, Dunworth M, Pflum MKH, Casero RA Jr, Perera L, Taylor WR, Tillekeratne LMV. A new class of cytotoxic agents targets tubulin and disrupts microtubule dynamics. Bioorg Chem. 2021 Nov;116:105297. doi: 10.1016/j.bioorg.2021.105297. Epub 2021 Aug 30. PMID: 34509798; PMCID: PMC8530978.
Karagiannis D, Rampias T. HDAC Inhibitors: Dissecting Mechanisms of Action to Counter Tumor Heterogeneity. Cancers (Basel). 2021 Jul 16;13(14):3575. doi: 10.3390/cancers13143575. PMID: 34298787; PMCID: PMC8307174.
Abbass, S., Hassan, H., Mohamed, M., Moustafa, G., Abuo-Rahma, G. (2019). 'Recent Prospectives of Anticancer Histone Deacetylase Inhibitors', Journal of advanced Biomedical and Pharmaceutical Sciences, 2(4), pp. 135-151. doi: 10.21608/jabps.2019.14468.1051.
Kaur R, Dwivedi AR, Kumar B, Kumar V. Recent Developments on 1,2,4-Triazole Nucleus in Anticancer Compounds: A Review. Anticancer Agents Med Chem. 2016;16(4):465-89. doi: 10.2174/1871520615666150819121106. PMID: 26286663.
Grytsai O, Valiashko O, Penco-Campillo M, Dufies M, Hagege A, Demange L, Martial S, Pagès G, Ronco C, Benhida R. Synthesis and biological evaluation of 3-amino-1,2,4-triazole derivatives as potential anticancer compounds. Bioorg Chem. 2020 Nov; 104:104271. doi: 10.1016/j.bioorg.2020.104271. Epub 2020 Sep 8. PMID: 32992279.
Halgren, T. A.; Murphy, R. B.; Friesner, R. A.; Beard, H. S.; Frye, L. L.; Pollard, W. T.; Banks, J. L., “Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening”, J. Med. Chem., 2004, 47, 1750–1759
Hai, Y., Christianson, D. Histone deacetylase 6 structure and molecular basis of catalysis and inhibition. Nat Chem Biol 12, 741–747 (2016). https://doi.org/10.1038/nchembio.2134
Lauffer BE, Mintzer R, Fong R, Mukund S, Tam C, Zilberleyb I, Flicke B, Ritscher A, Fedorowicz G, Vallero R, Ortwine DF, Gunzner J, Modrusan Z, Neumann L, Koth CM, Lupardus PJ, Kaminker JS, Heise CE, Steiner P. Histone deacetylase (HDAC) inhibitor kinetic rate constants correlate with cellular histone acetylation but not transcription and cell viability. J Biol Chem. 2013 Sep 13;288(37):26926-43. doi: 10.1074/jbc.M113.490706. Epub 2013 Jul 29. PMID: 23897821; PMCID: PMC3772242.
Somoza JR, Skene RJ, Katz BA, Mol C, Ho JD, Jennings AJ, Luong C, Arvai A, Buggy JJ, Chi E, Tang J, Sang BC, Verner E, Wynands R, Leahy EM, Dougan DR, Snell G, Navre M, Knuth MW, Swanson RV, McRee DE, Tari LW. Structural snapshots of human HDAC8 provide insights into the class I histone deacetylases. Structure. 2004 Jul;12(7):1325-34. doi: 10.1016/j.str.2004.04.012. PMID: 15242608.
Schrödinger Release 2024-1: QikProp, Schrödinger, LLC, New York, NY, 2024.
Bowers, K. J.; Chow, E.; Xu, H.; Dror, R. O.; Eastwood, M. P.; Gregersen, B. A.; Klepeis, J. L.; Kolossvary, I.; Moraes, M. A.; Sacerdoti, F. D.; Salmon, J. K.; Shan, Y.; Shaw, D. E., “Scalable algorithms for molecular dynamics simulations on commodity clusters”, Proceedings of the ACM/IEEE Conference on Supercomputing (SC06), Tampa, Florida, 2006, November 11-17
Ghosh AK, Shahabi D. Synthesis of amide derivatives for electron deficient amines and functionalized carboxylic acids using EDC and DMAP and a catalytic amount of HOBt as the coupling reagents. Tetrahedron Lett. 2021 Jan 19;63:152719. doi: 10.1016/j.tetlet.2020.152719. Epub 2020 Dec 25. PMID: 33456089; PMCID: PMC7808253.
Saeed AM, Al-Hamashi AA. Molecular Docking, ADMET Study, Synthesis, Characterization and Preliminary Antiproliferative Activity of Potential Histone Deacetylase Inhibitors with Isoxazole as New Zinc Binding Group. Iraqi Journal of Pharmaceutical Sciences (P-ISSN 1683-3597 E-ISSN 2521-3512). 2023 Nov 3;32(Suppl.):188-203.
Mosa HM, Al-Hamashi AA. Design, Synthesis, and Cytotoxicity Evaluation of Sulfonamide Derivatives as Potential HDAC Inhibitors. Azerbaijan Pharmaceutical and Pharmacotherapy Journal. 2023;22(2):214-7
Hadi, Mohammed & Hameed, Nedaa & A.Rahim, Nedaa & Sulaiman, Ahmed & Mohammed, Rusul & Ali, Hasan. (2022). Synthesis, Characterization and Preliminary Antimicrobial Evaluation of New Schiff bases and Aminothiadiazole Derivatives of N- Substituted Phthalimide. Research Journal of Pharmacy and Technology. 10.52711/0974-360X.2022.00647.
Al-Ali, A.A., Alsalami, K.A.S. and Athbi, A. M. (2022). Cytotoxic effects of CeO2 NPs and β- carotine and thier ability to induce apoptosis in human breast normal and cancer cell lines. Iraqi Journal of Science, V (63): 3.
Falih. S M., Al-saray S. T, Alfaris A. A. and Al-Ali A.A. (2022). The synergistic effect of eucalyptus oil and retinoic acid on human esophagus cancer cell line SK-GT-4. Egyptian journal of medical human genetics, V. 23:70
Al-Shammari, A.M.; Al-Ismaeel, W.N.; Al-Ali, A.A.;Hassan, A.A.and Ahmed , A.A.(2019). Enhancement of Oncolytic Activity of Newcastle Disease virus Through Combination with Retinoic Acid Against Digestive System Malignancies. Molecular Therapy 27(4S1):126-127.
Freshney, R.I. (2010). Culture of animal cells a manual of basic technique and specialized applications sixth edition, Wiley-Blackwell, P732.
Pollastri, Michael. (2010). Overview on the Rule of Five. Current protocols in pharmacology / editorial board, S.J. Enna (editor-in-chief) ... [et al.]. Chapter 9. Unit 9.12. 10.1002/0471141755.ph0912s49.
Alqosaibi AI, Abdel-Ghany S, Al-Mulhim F, Sabit H. Vorinostat enhances the therapeutic potential of Erlotinib via MAPK in lung cancer cells. Cancer Treat Res Commun. 2022; 30:100509. doi: 10.1.
Z.M. Mohammed, A.A.A. Al-Hamashi,Molecular docking, ADMET and molecular dynamics simulation studies for molecules with expected HDAC inhibition activity.Gomal Journal of Medical Science 22,2(2024)164-72.
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