Docking Study, Synthesis, Characterization and Preliminary Cytotoxic Evaluation of New 1,3,4- Thiadiazole Derivatives
Keywords:Anticancer, Thiadiazoles, MCF-7, HRT-18, Docking study
Objectives: This study has determined that these newly synthesized analogs hold promise as potential sources of novel anticancer agents for combating breast cancer.
Methods: We initiated our research by obtaining the crystal structure of Histone deacetylases (HDACs-8) bound with Vorinostat (SAHA) from the Protein Data Bank (PDB code 4QA0). Subsequently, we conducted docking experiments, which revealed that compounds (V c,s, V d,s, V c,t, and V d,t) exhibited favorable docking scores when compared to the standard. These compounds, synthesized through multi-step procedures involving the reaction of intermediate derivatives (IV c,d) with thiosemicarbazide or semicarbazide, were subjected to confirmation of their chemical structures using FT-IR and 1H NMR analysis.
Results: The results of our in-vitro cytotoxicity assay (MTT assay) highlighted that compounds V c,t and V d,t exhibited notable inhibition ratios in the breast cancer cell line (MCF-7), while V c,t displayed similar efficacy in human colon adenocarcinoma (HRT-18) compared to the control drug, Vorinostat (SAHA).
Conclusion: Our docking analysis led us to conclude that the C=S moiety demonstrated exceptional binding affinity to the zinc binding group of the HDAC enzyme, establishing multiple interaction modes. This finding suggests the potential of these compounds as valuable candidates in the development of anticancer treatments.
Baretti M, Azad NS. The role of epigenetic therapies in colorectal cancer. Current Problems in Cancer. 2018;42(6):530-47.
Baylin SB, Jones PA. Epigenetic determinants of cancer. Cold Spring Harbor perspectives in biology. 2016;8(9):a019505.
Bunkar N, Pathak N, Lohiya NK, Mishra PK. Epigenetics: A key paradigm in reproductive health. Clinical and Experimental Reproductive Medicine. 2016;43(2):59.
Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010;31(1):27-36.
Manal M, Manish K, Sanal D, Selvaraj A, Devadasan V, Chandrasekar M. Novel HDAC8 inhibitors: A multi-computational approach. SAR and QSAR in Environmental Research. 2017;28(9):707-33.
Parbin S, Kar S, Shilpi A, Sengupta D, Deb M, Rath SK, et al. Histone deacetylases: a saga of perturbed acetylation homeostasis in cancer. Journal of Histochemistry & Cytochemistry. 2014;62(1):11-33.
Ruijter AJd, GENNIP AHv, Caron HN, Kemp S, KUILENBURG ABv. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochemical Journal. 2003;370(3):737-49.
Zhou H, Wang C, Ye J, Chen H, Tao R. Design, virtual screening, molecular docking and molecular dynamics studies of novel urushiol derivatives as potential HDAC2 selective inhibitors. Gene. 2017; 637:63-71.
Eckschlager T, Plch J, Stiborova M, Hrabeta J. Histone deacetylase inhibitors as anticancer drugs. International journal of molecular sciences. 2017;18(7):1414.
Zwick V, Chatzivasileiou A-O, Deschamps N, Roussaki M, Simões-Pires CA, Nurisso A, et al. Aurones as histone deacetylase inhibitors: Identification of key features. Bioorganic & medicinal chemistry letters. 2014;24(23):5497-501.
Cappellacci L, Perinelli DR, Maggi F, Grifantini M, Petrelli R. Recent progress in histone deacetylase inhibitors as anticancer agents. Current medicinal chemistry. 2020;27(15):2449-93.
Yoon S, Kang G, Eom GH. HDAC inhibitors: therapeutic potential in fibrosis-associated human diseases. International journal of molecular sciences. 2019;20(6):1329.
Yu C, He F, Qu Y, Zhang Q, Lv J, Zhang X, et al. Structure optimization and preliminary bioactivity evaluation of N-hydroxybenzamide-based HDAC inhibitors with Y-shaped cap. Bioorganic & Medicinal Chemistry. 2018;26(8):1859-68.
Brindisi M, Senger J, Cavella C, Grillo A, Chemi G, Gemma S, et al. Novel spiroindoline HDAC inhibitors: Synthesis, molecular modelling and biological studies. European Journal of Medicinal Chemistry. 2018; 157:127-38.
Liu R, Wang J, Tang W, Fang H. Design and synthesis of a new generation of substituted purine hydroxamate analogs as histone deacetylase inhibitors. Bioorganic & Medicinal Chemistry. 2016;24(7):1446-54.
Manal M, Chandrasekar M, Priya JG, Nanjan M. Inhibitors of histone deacetylase as antitumor agents: A critical review. Bioorganic chemistry. 2016; 67:18-42.
Huang M, Zhang J, Yan C, Li X, Zhang J, Ling R. Small molecule HDAC inhibitors: Promising agents for breast cancer treatment. Bioorganic Chemistry. 2019; 91:103184.
Serban G, Stanasel O, Serban E, Bota S. 2-Amino-1, 3, 4-thiadiazole as a potential scaffold for promising antimicrobial agents. Drug design, development and therapy. 2018; 12:1545.
Wu Q, Cai H, Yuan T, Li S, Gan X, Song B. Novel vanillin derivatives containing a 1, 3, 4-thiadiazole moiety as potential antibacterial agents. Bioorganic & medicinal chemistry letters. 2020;30(10):127113.
Kasetti Ashok B, Singhvi I, Ravindra N, Shaik AB. Antimicrobial and antitubercular evaluation of some new 5-amino-1, 3, 4-thiadiazole-2-thiol derived Schiff bases. Rev Roum Chim. 2020;65(9):771-6.
Mali JK, Sutar YB, Pahelkar AR, Verma PM, Telvekar VN. Novel fatty acid‐thiadiazole derivatives as potential antimycobacterial agents. Chemical Biology & Drug Design. 2020;95(1):174-81.
El‐Hazek RM, El‐Sabbagh WA, El‐Hazek RM, El‐Gazzar MG. Anti‐inflammatory and analgesic effect of LD‐RT and some novel thiadiazole derivatives through COX‐2 inhibition. Archiv der Pharmazie. 2020;353(10):2000094.
Banik BK, Sahoo BM, Kumar B, Panda KC. Microwave Induced Green Chemistry Approach Towards the Synthesis of Heterocyclic Compounds via CN Bond Forming Reactions. Current Microwave Chemistry. 2021;8(3):204-14.
Malygin A. Study on the antiepyleptic activity of the new amide derivative of valproic acid and 1, 3, 4-thiadiazole. Epilepsy and paroxysmal conditions. 2020;11(4):357-63.
Zhang J, Wang X, Yang J, Guo L, Wang X, Song B, et al. Novel diosgenin derivatives containing 1, 3, 4-oxadiazole/thiadiazole moieties as potential antitumor agents: Design, synthesis and cytotoxic evaluation. European journal of medicinal chemistry. 2020; 186:111897.
Cascioferro S, Petri GL, Parrino B, Carbone D, Funel N, Bergonzini C, et al. Imidazo [2, 1-b][1, 3, 4] thiadiazoles with antiproliferative activity against primary and gemcitabine-resistant pancreatic cancer cells. European Journal of Medicinal Chemistry. 2020; 189:112088.
Perupogu N, Krishna CM, Ramachandran D. Design, synthesis and anticancer evaluation of 1, 2, 4-thiadiazole linked benzoxazole-quinazoline derivatives. Elsevier; 2020. p. 100482.
Azaam MM, Kenawy E-R, El-din ASB, Khamis AA, El-Magd MA. Antioxidant and anticancer activities of α-aminophosphonates containing thiadiazole moiety. Journal of Saudi Chemical Society. 2018;22(1):34-41.
Cevik UA, Osmaniye D, Levent S, Sağlik BN, Çavuşoğlu BK, Karaduman AB, et al. Synthesis and biological evaluation of novel 1, 3, 4-thiadiazole derivatives as possible anticancer agents. Acta Pharmaceutica. 2020;70(4):499-513.
Chidella K, Seelam N, Cherukumalli PKR, Reddy J, Sridhar G. Design and synthesis of novel 1, 2, 4-Thiadiazole linked imidazo [1, 2-b] pyridazine as anticancer agents. Chemical Data Collections. 2020; 30:100554.
Ding J, Liu J, Zhang Z, Guo J, Cheng M, Wan Y, et al. Design, synthesis and biological evaluation of coumarin-based N-hydroxycinnamamide derivatives as novel histone deacetylase inhibitors with anticancer activities. Bioorganic Chemistry. 2020; 101:104023.
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, et al. The protein data bank. Nucleic acids research. 2000;28(1):235-42.
Saloutin V, Burgart YV, Kuzueva O, Kappe C, Chupakhin O. Biginelli condensations of fluorinated 3-oxo esters and 1, 3-diketones. Journal of Fluorine Chemistry. 2000;103(1):17-23.
K Hameed K, HS Hussain F. Ultrasound-Assisted Synthesis of Some New N-(Substituted Carboxylic Acid-2-yl)-6-Methyl-4-Substituted Phenyl-3, 4-Dihydropyrimidine-2 (1H)-One Carboxamides. Eurasian Journal of Science and Engineering. 2018;4(2).
Barbosa G, de Aguiar A. Synthesis of 1, 3, 4-Thiadiazole Derivatives and Microbiological Activities: A Review. Revista Virtual de Química. 2019;11(3):806-48.
González-Martínez D, Fernández-Sáez N, Cativiela C, Campos JM, Gotor-Fernández V. Development of Biotransamination Reactions towards the 3, 4-Dihydro-2 H-1, 5-benzoxathiepin-3-amine Enantiomers. Catalysts. 2018;8(10):470.
Yang F, Zhao N, Song J, Zhu K, Jiang C-s, Shan P, et al. Design, synthesis and biological evaluation of novel coumarin-based hydroxamate derivatives as histone deacetylase (hdac) inhibitors with antitumor activities. Molecules. 2019;24(14):2569.
Deyrieux AF, Wilson VG. In vitro culture conditions to study keratinocyte differentiation using the HaCaT cell line. Cytotechnology. 2007;54(2):77–83.
Riss TL, Moravec RA, Niles AL, Duellman S, Benink HA, Worzella TJ, et al. Cell Viability Assays. Assay Guid Man [Internet]. 2016;1–25. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23805433.
Sarah S. Jabbar, Mohammed H.Mohammed. Coumarin based-histone deacetylase HADC inhibitors. Egyptian Journal of Chemistry. 2022;65(7)379-384.
Duraid Al-Amily, Mohammed H. Mohammed. Design, Synthesis and Cytotoxicity Study of Primary Amides as Histone Deacetylase Inhibitors. Iraqi J Pharm Sci. 2019.Vol.28(2) .
Othman M. Sagheer, Mohammed H. Mohammed, Jaafar S. Wadi, and Zaid O. Ibraheem. Studying the Cytotoxic Activity of Newly Designed and Synthesized HDAC 2100346.
Miller TA, Witter DJ, Belvedere S. Histone deacetylase inhibitors. Journal of medicinal chemistry. 2003;46(24):5097-116.
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