Design and synthesis of 2, 4 disubstituted thiazole derivatives as a potential anticancer agent: Molecular docking, synthesis, analysis, and biological activity study

Main Article Content

Prabodh V. Sapkale
Avinash V.Patil
Sandeep A. Patil

Keywords

thiazole derivatives, anticancer, EGFR inhibitors, molecular docking, Lipinski’s Rule

Abstract

Molecular docking studies were performed for the promising compounds to interpret their detected enzymatic activities based on their binding interactions with the receptor. Among the compounds studied, PVS 03 exhibited the highest docking score of -7.811 and had a strong affinity towards the receptor compared to other compounds. It also formed a hydrophobic bond with C10, C17, C18, and C14, which is essential for anticancer activity. All compounds were synthesized by the traditional synthesis method and the reaction was monitored by the TCL method. The percentage yield was calculated in that PVS 01 had a greater yield while PVS 04 showed a lower yield as shown in table 4, also % purity was carried out by the HPLC method in that PVS 10 have a greater purity while PVS 04 have less purity in the series of novel thiazole derivatives. Novel 2, 4 disubstituted thiazole derivatives were synthesized to screen their in vitro anticancer activity against Hep-G2 and MDAMB-231 cell lines. PVS 03 exhibited the best anticancer activity compared to dasatinib. However, PVS 06 and 07 showed no inhibition against MDAMB-231 cells, whilePVS01 to PVS 10 showed no inhibition against Hep-G2 cells. These previous encouraging results of biological evaluation of the newly synthesized thiazole could recommend an excellent framework for the detection of new potent antitumor leads. Overall, these findings suggest that the novel thiazole derivatives could be potential candidates for the development of EGFR inhibitors with improved anticancer activity.

Abstract 269 | PDF Downloads 23

References

1. Akram M, Iqbal M, Daniyal M, Khan AU. Awareness and current knowledge of breast cancer. Biological research. 2017;50:1-23.
2. Cheng F, Guo D. MET in glioma: signaling pathways and targeted therapies. Journal of Experimental & Clinical Cancer Research. 2019;38:1-3.
3. London M, Gallo E. Epidermal growth factor receptor (EGFR) involvement in epithelial‐derived cancers and its current antibody‐based immunotherapies. Cell biology international. 2020;44(6):1267-1282.
4. Shah RR, Shah DR. Safety and tolerability of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in oncology. Drug safety. 2019;42(2):181-198.
5. Rebuzzi SE, Alfieri R, La Monica S, Minari R, Petronini PG, Tiseo M. Combination of EGFR-TKIs and chemotherapy in advanced EGFR mutated NSCLC: Review of the literature and future perspectives. Critical Reviews in Oncology/Hematology. 2020;146:102820.
6. Arora P, Arora V, Lamba HS, Wadhwa D. Importance of heterocyclic chemistry: a review. International Journal of Pharmaceutical Sciences and Research. 2012;3(9):2947-2954.
7. Graham R. Lawton, Haitao Ji, Pavel Martáse,Linda J. Roman,and Richard B. Silverman,Synthesis and enzymatic evaluation of 2- and 4-aminothiazole-based inhibitors of neuronal nitric oxide synthase, Beilstein Journal of Organic Chemistry. 2009; 5-28
8. Burkhart BJ, Schwalen CJ, Mann G, Naismith JH, Mitchell DA. YcaO-dependent posttranslational amide activation: biosynthesis, structure, and function. Chemical reviews. 2017;117(8):5389-456.
9. SR Pattan, Synthesis and Biological Evaluation of Some Substituted Amino Thiazole Derivatives, Asian Journal of Research in Chemistry. 2009; 22: 196-201.
10. Grybaitė B, Vaickelionienė R, Stasevych M, Komarovska, Porokhnyavets O, Kantminienė K, Novikov V, Mickevičius V. Synthesis and antimicrobial activity of novel thiazoles with reactive functional groups. ChemistrySelect. 2019;4(23):6965-6970.
11. Chang-Ling Liu, Zheng-Ming Li, Synthesis and biological activity of novel 2- methyl-4-trifluoromethyl-thiazole-5-carboxamide derivatives, Journal of Fluorine Chemistry 125;2004:1287–1290.
12. A.Th. Chaviara, CopperII Schiff base coordination compounds of dien with heterocyclic aldehydes and 2-amino-5-methyl-thiazole: synthesis, characterization, antiproliferative and antibacterial studies. Crystal structure of CudienOOCl2, Journal of Inorganic Biochemistry. 98; 2004:1271–1283.
13. Gülhan Turan-Zitouni, Synthesis of some 2-[benzazole-2-ylthioacetylamino]thiazole derivatives and their antimicrobial activity and toxicity, European Journal of Medicinal Chemistry 39;2003:267–272.
14. Petrou A, Fesatidou M, Geronikaki A. Thiazole ring—A biologically active scaffold. Molecules. 2021;26(11):3166.
15. Kaur H, Goyal A. A review on thiazole as anticancer agents. International Journal of Pharmaceutical Drug Analysis. 2018;6:509-522. 16. Niu ZX, Wang YT, Zhang SN, Li Y, Chen XB, Wang SQ, Liu HM. Application and synthesis of thiazole ring in clinically approved drugs. European Journal of Medicinal Chemistry. 2023:115172.
17. Sharma PC, Bansal KK, Sharma A, Sharma D, Deep A. Thiazole-containing compounds as therapeutic targets for cancer therapy. European journal of medicinal chemistry. 2020 ;188:112016.
18. Kimber TB, Chen Y, Volkamer A. Deep learning in virtual screening: recent applications and developments. International Journal of Molecular Sciences. 2021;22(9):4435.
19. Lee K, Jeong KW, Lee Y, Song JY, Kim MS, Lee GS, Kim Y. Pharmacophore modeling and virtual screening studies for new VEGFR-2 kinase inhibitors. European journal of medicinal chemistry. 2010;45(11):5420-5427.
20. Singh N, Tiwari S, Srivastava KK, Siddiqi MI. Identification of novel inhibitors of Mycobacterium tuberculosis PknG using pharmacophore based virtual screening, docking, molecular dynamics simulation, and their biological evaluation. Journal of chemical information and modeling. 2015;55(6):1120-1129.
21. Gabr MT, El-Gohary NS, El-Bendary ER, El-Kerdawy MM, Ni N. Synthesis, in vitro antitumor activity and molecular modeling studies of a new series of benzothiazole Schiff bases. Chinese Chemical Letters. 2016;27(3):380-386.
22. A. Verma, Synthesis, characterization and biological evaluation of mutual prodrug of indomethacin and aminothiazole with reduced ulcerogenicity. AAPS. 2009;21-25.
23. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunological Methods. 1983 ;65(1-2):55-63.
24. Yuriev E, Holien J, Ramsland PA. Improvements, trends, and new ideas in molecular docking: 2012–2013 in review. Journal of Molecular Recognition. 2015;28(10):581-604.
25. Kar S, Leszczynski J. Open access in silico tools to predict the ADMET profiling of drug candidates. Expert opinion on drug discovery. 2020;15(12):1473-1487.
26. Chagas CM, Moss S, Alisaraie L. Drug metabolites and their effects on the development of adverse reactions: Revisiting Lipinski’s Rule of Five. International journal of pharmaceutics. 2018;549(1-2):133-149.