Synthesis and Biological Evaluation of Furyl-Carboxamide Derivatives as Potential Anticancer Agents

Abstract

Topoisomerase II (Top-II) is an essential therapeutic target in cancer treatment owing to its overexpression in a wide variety of cancerous cells, including colorectal and breast cancer. Significant efforts have been made to discover and develop competitive inhibitors of the Top-II enzyme as potential anticancer agents. Herein, molecular modeling was employed to identify a new series of furyl-2-carboxamide derivatives as potential anticancer agents. Compounds 3, 5, and 7 were synthesized and characterized with the aid of several spectroscopic techniques, such as FT-IR, NMR, and mass spectroscopy, as well as elemental analysis. The anticancer activity properties of compounds 3, 5, and 7 were evaluated in vitro using an MTT assay in a human colorectal HCT-116 cell line with different concentration dilutions. The results indicate that the anthraquinone compound 3 is 1.3-1.6 times more potent against human colon cancer HCT-116 cells than the pyridine and benzophenone compounds 7 and 5, respectively, which reveals the importance of the anthraquinone moiety in exerting the inhibitory activity of the compound. Our findings recommend that further optimization of this series would benefit colon cancer treatment.

Keywords

• Anticancer
• furyl-2-carboxamide
• docking
• MTT assay
• Top-II

Supporting Institution

Department of Applied Pharmaceutical Sciences and Clinical Pharmacy, Faculty of Pharmacy, Isra University

References

1. 1. Kumar S, Narasimhan B. Therapeutic potential of heterocyclic pyrimidine scaffolds. Chemistry Central Journal [Internet]. 2018 Dec [cited 2022 Jul 19];12(1):38.
2. 2. WHO. Cancer [Internet]. Cancer. 2022 [cited 2022 Jul 19].
3. 3. Sweidan K, Sabbah DA, Bardaweel S, Dush KA, Sheikha GA, Mubarak MS. Computer-aided design, synthesis, and biological evaluation of new indole-2-carboxamide derivatives as PI3Kα/EGFR inhibitors. Bioorganic & Medicinal Chemistry Letters [Internet]. 2016 Jun [cited 2022 Jul 19];26(11):2685–90.
4. 4. Sayed M, Kamal El-Dean AM, Ahmed M, Hassanien R. Synthesis of some heterocyclic compounds derived from indole as antimicrobial agents. Synthetic Communications [Internet]. 2018 Feb 16 [cited 2022 Jul 19];48(4):413–21.
5. 5. Irfan A, Batool F, Zahra Naqvi SA, Islam A, Osman SM, Nocentini A, et al. Benzothiazole derivatives as anticancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry [Internet]. 2020 Jan 1 [cited 2022 Jul 19];35(1):265–79.
6. 6. Ohba M, Oka T, Ando T, Arahata S, Ikegaya A, Takagi H, et al. Discovery and Synthesis of Heterocyclic Carboxamide Derivatives as Potent Anti-norovirus Agents. Chem Pharm Bull [Internet]. 2016 [cited 2022 Jul 19];64(5):465–75.
7. 7. Kassem AF, Nassar IF, Abdel-Aal MT, Awad HM, El-Sayed WA. Synthesis and Anticancer Activity of New ((Furan-2-yl)-1,3,4-thiadiazolyl)-1,3,4-oxadiazole Acyclic Sugar Derivatives. Chem Pharm Bull [Internet]. 2019 Aug 1 [cited 2022 Jul 19];67(8):888–95.
8. 8. Al-Najdawi M, Hiari Y, Qirim T, Shattat G, Al-Zweri M, Sheikha GA. Synthesis and Pharmacological Evaluation of Novel Unsubstituted Indole-Anthraquinone Carboxamide Derivatives as Potent Antihyperlipidemic Agents. Zeitschrift für Naturforschung C [Internet]. 2014 Feb 1 [cited 2022 Jul 19];69(1–2):21–8.

9. 9. Saleh MM. Development of a New Series of Bis-triazoles as Antitumour Agents [PhD thesis]. [UK]: University of Nottingham; 2014.
10. 10. Mosmann T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. Journal of Immunological Methods [Internet]. 1983 Dec [cited 2022 Jul 19];65(1–2):55–63.
11. 11. Saleh MM, Laughton CA, Bradshaw TD, Moody CJ. Development of a series of bis-triazoles as G-quadruplex ligands. RSC Adv [Internet]. 2017 [cited 2022 Jul 19];7(75):47297–308.
12. 12. Martin M, Ramos-Medina R, Bernat R, García-Saenz JA, del Monte-Millan M, Alvarez E, et al. Activity of docetaxel, carboplatin, and doxorubicin in patient-derived triple-negative breast cancer xenografts. Sci Rep [Internet]. 2021 Dec [cited 2022 Jul 19];11(1):7064.
13. 13. IARC. Cancer Today [Internet]. Cancer Today. 2020.
14. 14. Najdawi M. The synthesis of novel heterocyclic carboxamide derivatives and evaluation of their antihyperlipidemic and antioxidant activity [Internet] [PhD Thesis]. [Amman, Jordan]: Jordan university/ department of pharmacy; 2011.
15. 15. He ZX, Gong YP, Zhang X, Ma LY, Zhao W. Pyridazine as a privileged structure: An updated review on anticancer activity of pyridazine containing bioactive molecules. European Journal of Medicinal Chemistry [Internet]. 2021 Jan [cited 2022 Jul 19];209:112946.
16. 16. Musiol R. An overview of quinoline as a privileged scaffold in cancer drug discovery. Expert Opinion on Drug Discovery [Internet]. 2017 Jun 3 [cited 2022 Jul 19];12(6):583–97.
17. 17. Kumar D, Sharma P, Singh H, Nepali K, Gupta GK, Jain SK, et al. The value of pyrans as anticancer scaffolds in medicinal chemistry. RSC Adv [Internet]. 2017 [cited 2022 Jul 19];7(59):36977–99.