A series of novel thiosemicarbazide derivatives (2a-d) were synthesized from 3,5-bis(trifluoromethyl) benzohydrazide (1) and various substituted isothiocyanates. The structures of novel compounds were determined by analytical and spectral (IR, 1H-NMR, and elemental analysis) methods. In silico studies were conducted to determine and evaluate the potential anticancer activity of the compounds. Target-oriented drug design is crucial for cancer therapy for increasing the selectivity and consequently decreasing the adverse effects of anticancer agents. Computer-aided drug design technology enables us to design and develop target-oriented and hence, selective therapeutic agents. We benefited that technology during our drug design process and selected our targets as ATP-dependent enzyme topoisomerase II (Topo II), epidermal growth factor receptor (EGFR) tyrosine kinase domain, carbonic anhydrase IX and tubulin-colchicine: stathmin-like domain complex, which has significant roles in the cancer development process by their biochemical and physiological activities. In the light of the results obtained from in silico studies, the title compounds displayed significant potential activity about possessing the qualification of being multi-target drugs by effecting and hitting a few of the main targets of cancer chemotherapy together and at the same time.
___
1. Singhal S, Arora S, Agarwal S, et al. A review on potential biological activities of thiosemicarbazides. World J Pharm and Pharm Sci. 2013;2:4661-81.
2. Narang R, Narasimhan B, Sharma S. A review on biological activities and chemical synthesis of hydrazide derivatives. Curr Med Chem. 2012;19:569- 612.
3. Agata S, Staczek P, Stefańska J. Synthesis and structure-activity relationship studies of 4-arylthiosemicarbazides as topoisomerase IV inhibitors with grampositive antibacterial activity. Search for molecular basis of antibacterial activity of thiosemicarbazides. Eur J Med Chem. 2011;46:5717-26.
4. Patel DB, Patel KD, Prajapati NP, et al. Design, synthesis and biological in silico study of fluorine-containing quinoline hybrid thiosemicarbazide analogues J Heterocyc Chem. 2019;56:2235-52.
5. Pitucha M, Karczmarzyk Z, Swatko-Ossor M, et al. Synthesis, in vitro screening and docking studies of new thiosemicarbazide derivatives as antitubercular agents. Molecules. 2019;24:251.
6. Nevagi RJ, Dhake AS, Narkhede HI, et al. Design, synthesis and biological evaluation of novel thiosemicarbazide analogues as potent anticonvulsant agents. Bioorg Chem. 2014;54:68-72.
7. He J, Wang X, Zhao X, et al. Synthesis and antitumor activity of novel quinazoline derivatives containing thiosemicarbazide moiety Eur J Med Chem. 2012;54:925-30.
8. Šarkanj B, Molnar M, Čačić M, et al. 4-Methyl-7-hydroxycoumarin antifungal and antioxidant activity enhancement by substitution with thiosemicarbazide and thiazolidinone moieties. Food Chem. 2013;139:488-95.
9. Matsa R, Makam P, Kaushik M, et al. Thiosemicarbazone derivatives: Design, synthesis and in vitro antimalarial activity studies. Eur J Pharm Sci. 2019;137:104986.
10. Ulusoy Güzeldemirci N, Cimok S, Daş-Evcimen N, et al. Synthesis and aldose reductase inhibitory effect of some new hydrazinecarbothioamides and 4-thiazolidinones bearing an imidazo[2,1-b]thiazole moiety. Turk J Pharm Sci. 2019;16:1-7.
11. Cihan-Üstündağ G, Gürsoy E, Naesens L, et al. Synthesis and antiviral properties of novel indole-based thiosemicarbazides and 4-thiazolidinones. Bioorg Med Chem. 2016;24:240-46.
12. Ulusoy Güzeldemirci N, Küçükbasmacı Ö. Synthesis and antimicrobial activity evaluation of new 1,2,4-triazoles and 1,3,4-thiadiazoles bearing imidazo[2,1-b]thiazole moiety. Eur J Med Chem. 2010;45:63-8.
13. Ulusoy Güzeldemirci N, Şatana D, Küçükbasmacı Ö. Synthesis, characterization, and antimicrobial evaluation of some new hydrazinecarbothioamide, 1,2,4-triazole and 1,3,4-thiadiazole derivatives. J. Enzyme Inhib Med Chem. 2013;28:968-73.
14. Smart BE. Fluorine substituent effects (on bioactivity). J Fluor Chem. 2001;109:3-11.
15. Böhm HJ, Banner D, Bendels S, et al. Fluorine in medicinal chemistry. Chem Bio Chem. 2004;5:637-43.
16. Purser S, Moore PR, Swallow S, et al. Flourine in medicinal chemistry. Chem Soc Rev. 2008;37:320-30.
17. Weber GF. Why does cancer therapy lack effective anti-metastasis drugs? Cancer Lett. 2013;328:207-11.
18. Arora S, Agarwal S, Singhal S. Anticancer Activities of thiosemicarbazides/ thiosemicarbazones: a review. Int J Pharm Pharm. Sci. 2014;6:3-24.
19. Ooms F. Molecular modelling and computer aided drug design. Examples of their applications in medicinal chemistry. Curr Med Chem. 2000;7:141-58.
20. Baig MH, Ahmad K, Roy S, et al. Computer aided drug design: Success and limatations. Cur Pharm Des. 2016;22:572-81.
21. Macalino SJY, Gosu V, Hong S, et al. Role of computer-aided drug design in modern drug discovery. Arch Pharmacal Res. 2015;38:1686-701.
22. El-Zahabi HSA, Khalifa MMA, Gado YMH, et al. New thiobarbituric acid scaffold-based small molecules: Synthesis, cytotoxicity, 2D-QSAR, pharmacophore modelling and in-silico ADME screening. Eur J Pharm Sci. 2019;130:124-36.
23. Bai YB, Gao YQ, Nie XD, et al. Antifungal activity of griseofulvin derivatives against phytopathogenic fungi in vitro and in vivo and threedimensional quantitative structure-activity relationship analysis. J Agr Food Chem. 2019;67:6125-32.
24. Turkan F, Cetin A, Taslimi P, et al. Synthesis, biological evaluation and molecular docking of novel pyrazole derivatives as potent carbonic anhydrase and acetylcholinesterase inhibitors. Bioorg Chem. 2019;86:420-7.
25. Özdemir A, Sever B, Altıntop MD. New benzodioxole-based pyrazoline derivatives: Synthesis and anticandidal, in silico ADME, molecular docking studies. Lett Drug Des Discov. 2019;16:82-92.
26. Wei H, Ruthenburg AJ, Bechis SK, et al. Nucleotide-dependent domain movement in the ATPase domain of a human type IIA DNA topoisomerase. J Biol Chem. 2005;280:37041-37047.
27. Stamos J, Sliwkowski MX, Eigenbrot C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem. 2002;277:46265-72.
28. Alterio V, Hilvo M, Fiore AD, et al. Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX. Proc Natl Acad Sci. 2009;106:16233-238.
29. Ravelli RBG, Gigant B, Curmi PA, et al. Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature. 2004;428:198.
30. Kufareva I, Abagyan R. Methods of Protein Structure Comparison. In: Orry A., Abagyan R. (eds) Homology Modeling. Methods in Molecular Biology (Methods and Protocols), vol 857. Humana Press, 2011;231-57.
31. Maiorov VN, Crippen GM. Significance of root-mean-square deviation in comparing three-dimensional structures of globular proteins. J Mol Biol. 1994;235:625-34.
32. Coutsias EA, Seok C, Dill KA. Using quaternions to calculate rmsd. J Comput Chem. 2004;25:1849-57.