Synthesis and Pharmacological Study of Thiophene Derivatives
Abstract
In this study, the Gewald reaction was used to develop target compounds (RAA1-RAA9) in the quest for potentially active novel compounds with anti-cancer and antioxidant properties. The physicochemical and spectroanalytical studies of the synthesized derivatives verified their molecular structures. All synthesized compounds were chosen as prototypes by the NCI and tested for anti-cancer activity against a panel of cancer cell lines. The anti-cancer efficacy of the compounds was observed to be quite variable. Compound RAA5 was selected for a five-dose assay after showing strong anti-cancer activity in primary screening against all the cell lines. Additionally, the antioxidant activity of the compounds was determined by using a stable DPPH free radical as a radical scavenger. Compounds RAA5 and RAA7 exhibited excellent antioxidant activity, while other compounds of the series displayed satisfactory antioxidant activity compared to ascorbic acid. Our findings established the anti-cancer activity of novel thiophene derivatives, suggesting their potential for use in the development of new anti-cancer therapeutics.Keywords:
60 cell lines, Anticancer, Antioxidant, Gewald Reaction, NCI, SAR, Synthesis, ThiopheneReferences
1. Irfan A, Batool F, Zahra Naqvi SA, Islam A, Osman SM, Nocentini A, Alissa SA, Supuran CT. Benzothiazole derivatives as anticancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry 2020;35(1):265-279. Available from: doi.org/10.1080/14756366.2019.1698036
2. Abdel-Rahman SA, El-Damasy AK, Hassan GS, Wafa EI, Geary SM, Maarouf AR, Salem AK. Cyclohepta [b] thiophenes as Potential Antiproliferative Agents: Design, Synthesis, In Vitro, and In Vivo Anticancer Evaluation. ACS Pharmacology & Translational Science 2020;3(5):965-977. Available from: doi.org/10.1021/acsptsci.0c00096
3. Available URL from https://www.who.int/news-room/fact-sheets/detail/cancer. Accessed October 04, 2020.
4. McCutcheon M. Where have my eyebrows gone? One woman's personal experiences with chemotherapy. Florence, AL: Delmar Cengage Learning; 2001.
5. Anand P, Kunnumakara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, Sung B, Aggarwal BB. Cancer is a preventable disease that requires major lifestyle changes. Pharmaceutical Research 2008;25(9):2097-2116. Available from: doi.org/10.1007/s11095-008-9661-9
6. Sui X, Chen R, Wang Z, Huang Z, Kong N, Zhang M, Han W, Lou F, Yang J, Zhang Q, Wang X. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death & Disease. 2013;4(10):e838. Available from: doi.org/10.1038/cddis.2013.350
7. Marin JJ, Romero MR, Blazquez AG, Herraez E, Keck E, Briz O. Importance and limitations of chemotherapy among the available treatments for gastrointestinal tumours. Anti-Cancer Agents in Medicinal Chemistry 2009;9(2):162-184. Available from: doi.org/10.2174/187152009787313828
8. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nature Reviews Cancer 2012;12(4):237-251. Available from: doi.org/10.1038/nrc3237
9. Zimmermann S, Dziadziuszko R, Peters S. Indications and limitations of chemotherapy and targeted agents in non-small cell lung cancer brain metastases. Cancer Treatment Reviews 2014;40(6):716-722. Available from: doi.org/10.1016/j.ctrv.2014.03.005
10. Ismael GF, Rosa DD, Mano MS, Awada A. Novel cytotoxic drugs: old challenges, new solutions. Cancer Treatment Reviews 2008;34(1):81-91. Available from: doi.org/10.1016/j.ctrv.2007.08.001
11. Lu Y, Mahato RI. Pharmaceutical perspectives of cancer therapeutics. New York, NY: Springer; 2016.
12. Mishra R, Jha KK, Kumar S, Tomer I. Synthesis, properties and biological activity of thiophene: A review. Der Pharma Chemica 2011;3(4):38-54.
13. Mohammad AIC, Satyendra D, Apurba T, Patel M, Monika K, Girish K, Mohan S, Saravanan J. Synthesis and antimicrobial screening of some novel substituted thiophenes, Hygeia Journal of Drugs and Medicines 2012;4(1):112-118.
14. of Aguiar AC, of Moura RO, Junior JF, de Oliveira Rocha HA, Câmara RB, Schiavon MD. Evaluation of the antiproliferative activity of 2-amino thiophene derivatives against human cancer cells lines. Biomedicine & Pharmacotherapy 2016;84:403-414. Available from: doi.org/10.1016/j.biopha.2016.09.026
15. Liang C, Tang Z, Qian W, Shi C, Song H. Ultrasound-promoted synthesis of 2-aminothiophenes accelerated by DABCO utilizing PEG-200 as solvent. Journal of Chemical and Pharmaceutical Research 2014;6:798-802.
16. Abo-Salem HM, El-Sawy ER, Fathy A, Mandour AH. Synthesis, antifungal activity, and molecular docking study of some novel highly substituted 3-indolylthiophene derivatives. Egyptian Pharmaceutical Journal 2014;13(2):71-86. Available from: doi.org/10.4103/1687-4315.147064
17. Subba Rao D, Rasheed S, Thaslim Basha SK, Naga Raju C, Naresh K. SiO2/ZnCl2 catalyzed a-aminophosphonates and phosphonated N-(substituted phenyl) sulfonamides of 2-aminothiophene: Synthesis and biological evaluation. Der Pharma Chemica 2013;5:61-74.
18. Arora M, Saravanan J, Mohan S, Bhattacharjee S. Synthesis, Characterization and Antimicrobial Activity of Some Schiff Bases of 2-amino-4-(4-chlorophenyl)-n-(3-furan-2-ylmethyl carboxamido) thiophenes. Asian Journal of Research in Chemistry 2013;6(1):24-28.
19. da Franca Rodrigues KA, de Sousa Dias CN, do Nascimento Neris PL, da Câmara Rocha J, Scotti MT, Scotti L, Mascarenhas SR, Veras RC, de Medeiros IA, Keesen TD, de Oliveira TB. 2-Amino-thiophene derivatives present antileishmanial activity mediated by apoptosis and immunomodulation in vitro. European Journal of Medicinal Chemistry. 2015;106:1-4. Available from: doi.org/10.1016/j.ejmech.2015.10.011
20. Fortes AC, Almeida AA, Mendonca-Junior FJ, Freitas RM, Soares-Sobrinho JL, Soares MF. Anxiolytic properties of new chemical entity, 5TIO1. Neurochemical Research 2013;38(4):726-731. Available from: doi.org/10.1007/s11064-013-0970-y
21. Khan KM, Nullah Z, Lodhi MA, Jalil S, Choudhary MI, Rahman AU. Synthesis and anti-inflammatory activity of some selected aminothiophene analogs. Journal of Enzyme Inhibition and Medicinal Chemistry 2006;21(2):139-143. Available from: doi.org/10.1080/14756360500480418
22. Jagadish ER, Mohan S, Saravanan J, Satyendra D, Swetha Sree P, Apurba T, Manoj K, Rama Kanta S. Synthesis and in-vitro anti-platelet aggregation activity of some new substituted thiophenes. Hygeia Journal of Drugs and Medicines 2013;5:87-96.
23. Gouda MA, Eldien HF, Girges MM, Berghot MA. Synthesis and antioxidant activity of novel series of naphthoquinone derivatives attached to benzothiophene moiety. Medicinal Chemistry 2013;3(2):2228-2232. Available from: 10.4172/2161-0444.1000143
24. Hana HY, Khalil WK, Elmakawy AI, Elmegeed GA. Androgenic profile and genotoxicity evaluation of testosterone propionate and novel synthesized heterocyclic steroids. The Journal of Steroid Biochemistry and Molecular Biology 2008;110(3-5):284-294. Available from: doi.org/10.1016/j.jsbmb.2007.11.006
25. Duffy JL, Kirk BA, Konteatis Z, Campbell EL, Liang R, Brady EJ, Candelore MR, Ding VD, Jiang G, Liu F, Qureshi SA. Discovery and investigation of a novel class of thiophene-derived antagonists of the human glucagon receptor. Bioorganic & Medicinal Chemistry Letters 2005;15(5):1401-1405. Available from: doi.org/10.1016/j.bmcl.2005.01.003
26. Halliwell B. Biochemistry of oxidative stress. Biochemical Society Transactions 2007; 35(5): 1147-50. Available from: doi.org/10.1042/BST0351147
27. Pham-Huy LA, He H, Pham-Huy C. Free radicals, antioxidants in disease and health. International Journal of Biomedical Science 2008;4(2):89-96.
28. Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O. Oxidative stress and antioxidant defense. World Allergy Organization Journal 2012;5(1):9-19. Available from: 10.1097/WOX.0b013e3182439613
29. Pisoschi AM, Pop A. The role of antioxidants in the chemistry of oxidative stress: A review. European Journal of Medicinal Chemistry 2015;97:55-74. Available from: doi.org/10.1016/j.ejmech.2015.04.040
30. Singh PK. Histone methyl transferases: A class of epigenetic opportunities to counter uncontrolled cell proliferation. European Journal of Medicinal Chemistry 2019;166:351-368. Available from: doi.org/10.1016/j.ejmech.2019.01.069
31. Monks A, Scudiero D, Skehan P, Shoemaker R, Paull K, Vistica D, Hose C, Langley J, Cronise P, Vaigro-Wolff A, Gray-Goodrich M. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. Journal of the National Cancer Institute 1991;83(11):757-66. Available from: 10.1093/jnci/83.11.757
32. Boyd MR, Paull KD. Some practical considerations and applications of the National Cancer Institute in vitro anticancer drug discovery screen. Drug Development Research 1995;34(2):91-109. Available from: doi.org/10.1002/ddr.430340203
33. Boyd MR. Status of the NCI preclinical antitumor drug discovery screen. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology Updates. Philadelphia: Lippincott. 1989;3(10):1-12.
34. Gundogdu-Karaburun N, Cagri Karaburun A, Demirayak S, Kayagil I, Yurttas L. Synthesis and anticancer activity of some 2-[3/4-(2-substituted phenyl-2-oxoethoxy) benzylidene]-6-substituted-2, 3-dihydro-1H-inden-1-one derivatives. Letters in Drug Design & Discovery. 2014;11(5):578-585. Available from: 10.2174/1570180811666140403001212
35. Shimada K, Fujikawa K, Yahara K, Nakamura T. Antioxidative properties of xanthan on the autoxidation of soybean oil in cyclodextrin emulsion. Journal of Agricultural and Food Chemistry 1992;40(6):945-948. Available from: doi.org/10.1021/jf00018a005
36. Shah R, Verma PK. Synthesis of thiophene derivatives and their anti-microbial, antioxidant, anticorrosion and anticancer activity. BMC Chemistry. 2019;13(1):1-13.
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