Design, Synthesis, and Preliminary Antiproliferative Evaluation of 1,2,4-Thiadiazole Derivatives as Possible Histone Deacetylase Inhibitors
DOI:
https://doi.org/10.31351/vol33iss(4SI)pp57-66Keywords:
Histone Deacetylase, Molecular Docking, VorinostatAbstract
Histone deacetylases (HDACs) are a class of proteins that responsible of the hydrolysis of N-acetyl lysine residues in histones as well as non-histone protein substrates. This phenomenon may provide an explanation for the involvement of these enzymes in a wide range of clinical situations, encompassing cancer, metabolic, cardiovascular problems, and neurological diseases. Most of HDAC inhibitors are often used in clinical settings consist of a hydroxamate group (ZBG) that binds to zinc ion inside the active site. The poor selectivity and pharmacokinetic characteristics of numerous medicines belonging to the hydroxamates group have prompted the exploration of non-hydroximic ZBG HDAC inhibitors with a potential selectivity and potency profile. Therefore, the objective of this work is to design new HDAC inhibitors incorporating thiadiazole moiety as a ZBG. This study involved the design and virtual analysis of a series of thiadiazole derivatives using Maestro software. Compounds with good docking score which include compound 6a [4- (benzyloxy)-N-(1,2,4-thiadiazol-5-yl)benzamide] with docking score -8.953 kcal/mol and compound 6b [4-(naphthalen-1-ylmethoxy)-N-(1,2,4-thiadiazol-5- yl)benzamide] with docking score -9.290 kcal/mol and compound 6c[ 4-((4-methoxybenzyl)oxy)benzoic acid] with docking score -8.57 kcal/mol while the FDA approved vorinostat has a docking score -5.613 kcal/mol against HDAC 2 (4LXZ). Compound 6a, 6b and 6c were subjected to the organic synthesis applying traditional chemical reactions. The synthesis was commenced with the ether formation using Williamson reaction by reacting benzylic bromide derivatives with methyl 4-hydroxybenzoate, then the intermediates underwent ester hydrolysis to produce 4-(benzyloxy)benzoic acid derivatives and then reacted with 1,2,4-thiadiazol-5- amine by forming amide using 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) as coupling reagent. The intermediates and final products were characterized by FT-IR and NMR spectroscopy. The cytotoxic effect was assessed using the MTT cell viability assay indicate that IC50 of 6b is 0.66 μM while the IC50 of vorinostat is 1.48 μM.
How to Cite
Publication Dates
Received
Revised
Accepted
Published Online First
References
Tillekeratne LMV, Al-Hamashi AA, Dlamini S, Taylor W, Koranne R, Pflum MK, et al. In Search of Selectivity: Design, Synthesis, and Biological Evaluation of New Classes of HDAC Inhibitors, Proceedings, 2019, 22(1):63.
Al-Hamashi AA, Abdulhadi SL, Ali RMH. Evaluation of Zinc Chelation Ability for Non-Hydroxamic Organic Moieties. Egypt J Chem. 2023;66(5):215–21.
Hasan Y, Al-Hamashi A. Identification of Selisistat Derivatives as SIRT1-3 Inhibitors by in Silico Virtual Screening. Turkish Comput Theor Chem. 2023 Jul 4;8(2):1–11.
Saeed AM, Al-Hamashi AAA. Molecular Docking, ADMET Study, Synthesis, Characterization, and Preliminary Antiproliferative Activity of Potential Histone Deacetylase Inhibitors with Isoxazole as New Zinc Binding Group. Iraqi J Pharm Sci. 2023;32:188–203.
Cheng Y, He C, Wang M, Ma X, Mo F, Yang S, et al. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduct Target Therapy. 2019;4(1):62-68.
Saeed AM, Al-Hamashi AAA. Docking, ADMET Study, Synthesis and Biological Evaluation of Isoxazole Derivatives as Potential Histone Deacetylase Inhibitors. History of Medicine, 2023;9(1):2501–2508.
Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnology. 2010;28(10):1057–68.
Sagheer OM, Mohammed MH, Ibraheem ZO, Wadi JS, Tawfeeq MF. Synthesis of gamma biguanides butyric acid analogues as HDAC inhibitors and studying their cytotoxic activity. Material Today Proceeding. 2021;47:5983–91.
Al-Amily D, Mohammed MH. Design, synthesis and cytotoxicity study of primary amides as histone deacetylase inhibitors. Iraqi J Pharm Sci. 2019;28(2):151–8.
Sagheer O, Mohammed M, Wadi J, Ibraheem Z. Studying the Cytotoxic Activity of Newly Designed and Synthesized HDAC Inhibitors Derivatives of Pentanoyl Anilide‐5‐Biguanide. Macromol Symp. 2022 Feb 1;401:2100346.
Li Y, Geng J, Liu Y, Yu S, Zhao G. Thiadiazole-a Promising Structure in Medicinal Chemistry. ChemMedChem. 2013;8(1):27–41.
Lauffer BEL, Mintzer R, Fong R, Mukund S, Tam C, Zilberleyb I, et al. Histone deacetylase (HDAC) inhibitor kinetic rate constants correlate with cellular histone acetylation but not transcription and cell viability. J Biol Chem. 2013;288(37):26926–43.
Marek M, Shaik TB, Heimburg T, Chakrabarti A, Lancelot J, Ramos-Morales E, et al. Characterization of Histone Deacetylase 8 (HDAC8) Selective Inhibition Reveals Specific Active Site Structural and Functional Determinants. J Med Chem. 2018 Nov 21;61(22):10000–16.
Hai Y, Christianson DW. Histone deacetylase 6 structure and molecular basis of catalysis and inhibition. Nat Chem Biol. 2016;12(9):741–7.
Madhavi Sastry G, Adzhigirey M, Day T, Annabhimoju R, Sherman W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J Comput Aided Mol Des. 2013;27(3):221–34.
Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, et al. Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein−Ligand Complexes. J Med Chem. 2006 Oct 1;49(21):6177–96.
Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, et al. Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy. J Med Chem. 2004 Mar 1;47(7):1739–49.
Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, et al. Glide: A New Approach for Rapid, Accurate Docking and Scoring. 2. Enrichment Factors in Database Screening. J Med Chem. 2004 Mar 1;47(7):1750–9.
Yadav R, Imran M, Dhamija P, Chaurasia DK, Handu S. Virtual screening, ADMET prediction and dynamics simulation of potential compounds targeting the main protease of SARS-CoV-2. J Biomol Struct Dyn . 2021 Nov 22;39(17):6617–32.
Bowers KJ, Chow E, Xu H, Dror RO, Eastwood MP, Gregersen BA, et al. Scalable algorithms for molecular dynamics simulations on commodity clusters. Proceedings of the 2006 ACM/IEEE Conference on Supercomputing. New York, NY, USA: Association for Computing Machinery; 2006. p. 84–es. (SC ’06).
Kazemi M, Noori Z, Kohzadi H, Sayadi M, Kazemi A. A mild and efficient procedure for the synthesis of ethers from various alkyl halides. Chem Commun. 2013;1(841):43–50.
Orlowska E, Roller A, Wiesinger H, Pignitter M, Jirsa F, Krachler R, et al. Benzoic hydroxamate-based iron complexes as model compounds for humic substances: Synthesis, characterization and algal growth experiments. RSC Adv. 2016;6(46):40238–49.
Arrata I, Grison CM, Coubrough HM, Prabhakaran P, Little MA, Tomlinson DC, et al. Control of conformation in α-helix mimicking aromatic oligoamide foldamers through interactions between adjacent side-chains. Org Biomol Chem. 2019;17(15):3861–7.
Al-Ali AAA, Alsalami KAS, Athbi AM. Cytotoxic effects of CeO2 NPs and β-Carotene and their ability to induce apoptosis in human breast normal and cancer cell lines. Iraqi J Sci. 2022;63(3):923–37.
Mosa HM, Al-Hamashi AAA. Design, Synthesis, and Cytotoxicity Evaluation of Sulfonamide Derivatives as Potential HDAC Inhibitors. Azerbaijan Pharm Pharmacotherapy Journal. 2023;22(2):214–7.
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Iraqi Journal of Pharmaceutical Sciences
This work is licensed under a Creative Commons Attribution 4.0 International License.
