Research Article
Synthesis, Characterization, Antioxidant, and Anticancer Studies of Benzimidazole-Thiadiazole Derivatives
Abstract
In our study, some benzimidazole-thiadiazole derivative compounds were designed to develop new anticancer drugs, and their structures were proven by 1H-NMR, 13C-NMR, and elemental analysis spectral data. The cytotoxic activities of the compounds were evaluated by comparing the reference compound fluorouracil using the MTT method on the HT29 cell line. In addition, the cytotoxic effect of the compounds against the L929 (healthy mouse fibroblast cell) cell line was evaluated in order to determine the selectivity of the compounds. When the IC50 values of the compounds are examined, the structure of 5-(2-(2,6-dimethoxyphenyl)-1H-benz[d]imidazol-5(6)-yl)-N-cyclohexyl-1,3,4-thiadiazol-2-amine (BT-2) compound with an IC50 value of 34.13±2.48 µM showed comparable efficacy to the reference drug fluorouracil (12.84 ± 3.66 µM). It was determined that the cytotoxic effect of BT-2 compound on L929 healthy cell line was lower than the reference drug. These results are promising in terms of improving the anticancer effect of BT-2 compound. In addition, TAS and TOS of the compounds and antioxidant properties of the compounds were evaluated. The TOS value of the BT-2 compound appears to be comparable to the control drug.
Keywords
References
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- Parkin, D. M. (2001). Global cancer statistics in the year 2000. Lancet Oncology, 2(10), 596-596.
- Aydemir, N., & Bilaloğlu, R. (2003). Genotoxicity of two anticancer drugs, gemcitabine and topotecan, in mouse bone marrow in vivo. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 537(1), 43-51.
- Klevens, R. M., Morrison, M. A., Nadle, J., Petit, S., Gershman, K., Ray, S., ... & Active Bacterial Core surveillance (ABCs) MRSA Investigators. (2007). Invasive methicillin-resistant Staphylococcus aureus infections in the United States. Jama, 298(15), 1763-1771.
- El-Kalyoubi, S., Agili, F., Adel, I., & Tantawy, M. A. (2021). Novel Uracil Derivatives Depicted Potential Anticancer Agents: In Vitro, Molecular Docking, and ADME Study. Arabian Journal of Chemistry, 103669.
- Nazir, A., Mustafa, R., & Iqbal, M. (2021). In vitro & In vivo Phytochemical Evaluation of Bioactive Components Against Hyperglycemic-induced Oxidative Stress in Streptozocin Rat Model: A histopathological investigation. Biointerface Research in Applied Chemistry, 20, 7321-7341.
- Mousavi, S. M., Zarei, M., Hashemi, S. A., Babapoor, A., & Amani, A. M. (2019). A conceptual review of rhodanine: current applications of antiviral drugs, anticancer and antimicrobial activities. Artificial cells, nanomedicine, and biotechnology, 47(1), 1132-1148.
- Penning, T. D., Zhu, G. D., Gandhi, V. B., Gong, J., Liu, X., Shi, Y., ... & Giranda, V. L. (2009). Discovery of the poly (ADP-ribose) polymerase (PARP) inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the treatment of cancer. Journal of Medicinal Chemistry, 52(2), 514-523.
- Romero-Castro, A., León-Rivera, I., Ávila-Rojas, L. C., Navarrete-Vázquez, G., & Nieto-Rodríguez, A. (2011). Synthesis and preliminary evaluation of selected 2-aryl-5 (6)-nitro-1H-benzimidazole derivatives as potential anticancer agents. Archives of pharmacal research, 34(2), 181-189.
- Abdel-Mohsen, H. T., Ragab, F. A., Ramla, M. M., & El Diwani, H. I. (2010). Novel benzimidazole–pyrimidine conjugates as potent antitumor agents. European journal of medicinal chemistry, 45(6), 2336-2344.
- Demirayak, Ş., Mohsen, U. A., & Karaburun, A. Ç. (2002). Synthesis and anticancer and anti-HIV testing of some pyrazino [1, 2-a] benzimidazole derivatives. European Journal of Medicinal Chemistry, 37(3), 255-260.
- Demirayak, S., Kayagil, I., & Yurttas, L. (2011). Microwave supported synthesis of some novel 1, 3-Diarylpyrazino [1,2-a] benzimidazole derivatives and investigation of their anticancer activities. European Journal of Medicinal Chemistry, 46(1), 411-416.
- Galal, S. A., Hegab, K. H., Hashem, A. M., & Youssef, N. S. (2010). Synthesis and antitumor activity of novel benzimidazole-5-carboxylic acid derivatives and their transition metal complexes as topoisomerease II inhibitors. European Journal of Medicinal Chemistry, 45(12), 5685-5691.
- Moriarty, E., Carr, M., Bonham, S., Carty, M. P., & Aldabbagh, F. (2010). Synthesis and toxicity towards normal and cancer cell lines of benzimidazolequinones containing fused aromatic rings and 2-aromatic ring substituents. European Journal of Medicinal Chemistry, 45(9), 3762-3769.
- Yılmaz, Ü., Apohan, E., Küçükbay, H., Yılmaz, Ö., Tatlıcı, E., Yeşilada, Ö. (2022). Synthesis a Group of 5(6)-Substituted Benzimidazole Zn(II) and Co(II) Complexes and Investigation Their Cytotoxic and Antimicrobial Activities. Journal of Heterocyclic Chemistry, 1–6.
- Küçükbay, H., Uçkun, M., Apohan, E., & Yeşilada, Ö. (2021). Cytotoxic and Antimicrobial Potential of Benzimidazole Derivatives.Archiv Der Pharmazie, 354 (8), 1–8.
- Yılmaz, Ü., Tekin, S., Buğday, N., Yavuz, K., Küçükbay, H., & Sandal, S. (2019). Synthesis and evaluation of anticancer propereties of novels benzimidazole ligand and their cobalt(II) and zinc(II) complexes against cancer cell lines A-2780 and DU-145. Inorganica Chimica Acta, 495, 118977.
- Apohan, E., Yılmaz, Ü., Yılmaz, Ö., Serindağ, A., Küçükbay, H., Yeşilada, Ö., & Baran, Y. (2017). Synthesis, cytotoxic and antimicrobial activities of novel cobalt and zinc complexes of benzimidazole derivatives, Journal of Organometallic Chemistry, 828, 52-58.
- Kumar, B. V. S., Vaidya, S. D., Kumar, R. V., Bhirud, S. B., & Mane, R. B. (2006). Synthesis and anti-bacterial activity of some novel 2-(6-fluorochroman-2-yl)-1-alkyl/acyl/aroyl-1H-benzimidazoles. European Journal of Medicinal Chemistry, 41(5), 599-604.
- Kilcigil, G.A., & Altanlar, N. (2006). Synthesis and antifungal properties of some benzimidazole derivatives. Turkish Journal of Chemistry, 30(2), 223-228.
- Kerimov, I., Ayhan-Kilcigil, G., Can-Eke, B., Altanlar, N., & İscan, M. (2007). Synthesis, antifungal and antioxidant screening of some novel benzimidazole derivatives. Journal of Enzyme Inhibition and Medicinal Chemistry, 22(6), 696-701.
- Sharma, D., Narasimhan, B., Kumar, P., Judge, V., Narang, R., De Clercq, E., & Balzarini, J. (2009). Synthesis, antimicrobial and antiviral activity of substituted benzimidazoles. Journal of Enzyme Inhibition and Medicinal Chemistry, 24(5), 1161-1168.
- Kus, C., Ayhan-Kilcigil, G., & Eke, B. C. (2004). Synthesis and antioxidant properties of some novel benzimidazole derivatives on lipid peroxidation in the rat liver. Archives of Pharmacal Research, 27(2), 156-163.
- Kuş, C., Ayhan-Kılcıgil, G., Özbey, S., Kaynak, F. B., Kaya, M., Çoban, T., & Can-Eke, B. (2008). Synthesis and antioxidant properties of novel N-methyl-1, 3, 4-thiadiazol-2-amine and 4-methyl-2H-1,2,4-triazole-3 (4H)-thione derivatives of benzimidazole class. Bioorganic & Medicinal Chemistry, 16(8), 4294-4303.
- Buğday, N., Küçükbay, F., Apohan, E., Küçükbay, H., Serindağ, A., & Yeşilada, Ö. (2017). Synthesis and Evaluation of Novel Benzimidazole Conjugates Incorporating Amino Acids and Dipeptide Moieties. Letters in Organic Chemistry, 14, 198-206.
- [26] Shrivastava, N., Naim, M.J., Alam, M.J., Nawaz, F., Ahmed, S., & Alam, O. (2017). Benzimidazole scaffold as anticancer agent: synthetic approaches and structure– activity relationship. Archiv der Pharmazie, 350 (6), e201700040.
- [27] Gryshchenko, A.A., Tarnavskiy, S.S., Levchenko, K.V., Bdzhola, V.G., Volynets, G.P., Golub, A.G., Ruban, T.P., Vygranenko, K.V., Lukash, L.L., & Yarmoluk, S.M. (2016). Design, synthesis and biological evaluation of 5-amino-4-(1Hbenzoimidazol-2-yl)-phenyl-1, 2-dihydro-pyrrol-3-ones as inhibitors of protein kinase FGFR1. Bioorganic & Medicinal Chemistry, 24 (9), 2053-2059.
- Abdullaziz, M.A., Abdel-Mohsen, H.T., El Kerdawy, A.M., Ragab, F.A., Ali, M. M., Abu-bakr, S.M., Girgis, A.S., & El Diwani, H. I. (2017). Design, synthesis, molecular docking and cytotoxic evaluation of novel 2-furybenzimidazoles as VEGFR-2 inhibitors. European Journal of Medicinal Chemistry, 136, 315-329.
- El-Gohary, N.S., & Shaaban, M.I. (2017). Synthesis and biological evaluation of a new series of benzimidazole derivatives as antimicrobial, antiquorum-sensing and antitumor agents. European Journal of Medicinal Chemistry, 131, 255-262.
- El-Gohary, N.S. & Shaaban, M.I. (2017). Synthesis, antimicrobial, antiquorumsensing and antitumor activities of new benzimidazole analogs. European Journal of Medicinal Chemistry, 137, 439-449.
- Chojnacki, K., Wińska, P., Skierka, K., Wielechowska, M., & Bretner, M. (2017). Synthesis, in vitro antiproliferative activity and kinase profile of new benzimidazole and benzotriazole derivatives. Bioorganic Chemistry, 72, 1-10.
- Abdelgawad, M.A., Bakr, R.B., & Omar, H.A. (2017). Design, synthesis and biological evaluation of some novel benzothiazole/benzoxazole and/or benzimidazole derivatives incorporating a pyrazole scaffold as antiproliferative agents. Bioorganic Chemistry, 74, 82-90.
- Çevik, U.A., Sağlık, B.N., Korkut, B., Özkay, Y., & Ilgın, S. (2018). Antiproliferative, cytotoxic, and apoptotic effects of new benzimidazole derivatives bearing hydrazone moiety. Journal of Heterocyclic Chemistry, 55 (1), 138-148.
Benzimidazol-Tiyadiazol Türevlerinin Sentezi, Karakterizasyonu, Antioksidan ve Antikanser Çalışmaları
Abstract
Çalışmamızda yeni antikanser ilaçlar geliştirmek üzere bazı benzimidazol-tiyadiazol türevi bileşikler tasarlanmış ve yapıları 1H-NMR,13C-NMR ve elemental analiz spektral verileriyle kanıtlanmıştır. Bileşiklerin sitotoksik aktiviteleri HT29 hücre hattı üzerinde MTT yöntemi kullanılarak referans bileşik florourasilile kıyaslanarak değerlendirilmiştir. Ayrıca, bileşiklerin seçiciliklerini tespit etmek amacıyla L929 (sağlıklı fare fibroblast hücresi) hücre hattına karşı sitotoksik etkisi değerlendirilmiştir. Bileşiklerin IC50 değerleri incelendiğinde, 5-(2-(2,6-dimetoksifenil)-1H-benz[d]imidazol-5(6)-il)-N-siklohekzil-1,3,4-tiyadiazol-2-amin yapısına sahip BT-2 bileşiği 34,13±2,48 µM IC50 değeri ile referans ilaç fluorourasil (12,84 ± 3,66 µM) ile kıyaslanabilir etki göstermiştir. BT-2 bileşiğinin L929 sağlıklı hücre hattı üzerindeki sitotoksik etkisinin referans ilaçtan daha düşük olduğu tespit edilmiştir. Bu sonuçlar, BT-2 bileşiğinin antikanser etkisinin geliştirilebilmesi konusunda umut vericidir. Ayrıca, TAS ve TOS ile bileşiklerin antioksidan özellikleri değerlendirilmiştir. BT-2 bileşiğinin TOS değerinin kontrol ilaçla karşılaştırılabilir düzeyde olduğu görülmüştür.
References
- Bagi, C.M. (2002). Summary-Cancer cell metastasis session. Journal of Musculoskeletal And Neuronal Interactions, 2, 579-580.
- Parkin, D. M. (2001). Global cancer statistics in the year 2000. Lancet Oncology, 2(10), 596-596.
- Aydemir, N., & Bilaloğlu, R. (2003). Genotoxicity of two anticancer drugs, gemcitabine and topotecan, in mouse bone marrow in vivo. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 537(1), 43-51.
- Klevens, R. M., Morrison, M. A., Nadle, J., Petit, S., Gershman, K., Ray, S., ... & Active Bacterial Core surveillance (ABCs) MRSA Investigators. (2007). Invasive methicillin-resistant Staphylococcus aureus infections in the United States. Jama, 298(15), 1763-1771.
- El-Kalyoubi, S., Agili, F., Adel, I., & Tantawy, M. A. (2021). Novel Uracil Derivatives Depicted Potential Anticancer Agents: In Vitro, Molecular Docking, and ADME Study. Arabian Journal of Chemistry, 103669.
- Nazir, A., Mustafa, R., & Iqbal, M. (2021). In vitro & In vivo Phytochemical Evaluation of Bioactive Components Against Hyperglycemic-induced Oxidative Stress in Streptozocin Rat Model: A histopathological investigation. Biointerface Research in Applied Chemistry, 20, 7321-7341.
- Mousavi, S. M., Zarei, M., Hashemi, S. A., Babapoor, A., & Amani, A. M. (2019). A conceptual review of rhodanine: current applications of antiviral drugs, anticancer and antimicrobial activities. Artificial cells, nanomedicine, and biotechnology, 47(1), 1132-1148.
- Penning, T. D., Zhu, G. D., Gandhi, V. B., Gong, J., Liu, X., Shi, Y., ... & Giranda, V. L. (2009). Discovery of the poly (ADP-ribose) polymerase (PARP) inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the treatment of cancer. Journal of Medicinal Chemistry, 52(2), 514-523.
- Romero-Castro, A., León-Rivera, I., Ávila-Rojas, L. C., Navarrete-Vázquez, G., & Nieto-Rodríguez, A. (2011). Synthesis and preliminary evaluation of selected 2-aryl-5 (6)-nitro-1H-benzimidazole derivatives as potential anticancer agents. Archives of pharmacal research, 34(2), 181-189.
- Abdel-Mohsen, H. T., Ragab, F. A., Ramla, M. M., & El Diwani, H. I. (2010). Novel benzimidazole–pyrimidine conjugates as potent antitumor agents. European journal of medicinal chemistry, 45(6), 2336-2344.
- Demirayak, Ş., Mohsen, U. A., & Karaburun, A. Ç. (2002). Synthesis and anticancer and anti-HIV testing of some pyrazino [1, 2-a] benzimidazole derivatives. European Journal of Medicinal Chemistry, 37(3), 255-260.
- Demirayak, S., Kayagil, I., & Yurttas, L. (2011). Microwave supported synthesis of some novel 1, 3-Diarylpyrazino [1,2-a] benzimidazole derivatives and investigation of their anticancer activities. European Journal of Medicinal Chemistry, 46(1), 411-416.
- Galal, S. A., Hegab, K. H., Hashem, A. M., & Youssef, N. S. (2010). Synthesis and antitumor activity of novel benzimidazole-5-carboxylic acid derivatives and their transition metal complexes as topoisomerease II inhibitors. European Journal of Medicinal Chemistry, 45(12), 5685-5691.
- Moriarty, E., Carr, M., Bonham, S., Carty, M. P., & Aldabbagh, F. (2010). Synthesis and toxicity towards normal and cancer cell lines of benzimidazolequinones containing fused aromatic rings and 2-aromatic ring substituents. European Journal of Medicinal Chemistry, 45(9), 3762-3769.
- Yılmaz, Ü., Apohan, E., Küçükbay, H., Yılmaz, Ö., Tatlıcı, E., Yeşilada, Ö. (2022). Synthesis a Group of 5(6)-Substituted Benzimidazole Zn(II) and Co(II) Complexes and Investigation Their Cytotoxic and Antimicrobial Activities. Journal of Heterocyclic Chemistry, 1–6.
- Küçükbay, H., Uçkun, M., Apohan, E., & Yeşilada, Ö. (2021). Cytotoxic and Antimicrobial Potential of Benzimidazole Derivatives.Archiv Der Pharmazie, 354 (8), 1–8.
- Yılmaz, Ü., Tekin, S., Buğday, N., Yavuz, K., Küçükbay, H., & Sandal, S. (2019). Synthesis and evaluation of anticancer propereties of novels benzimidazole ligand and their cobalt(II) and zinc(II) complexes against cancer cell lines A-2780 and DU-145. Inorganica Chimica Acta, 495, 118977.
- Apohan, E., Yılmaz, Ü., Yılmaz, Ö., Serindağ, A., Küçükbay, H., Yeşilada, Ö., & Baran, Y. (2017). Synthesis, cytotoxic and antimicrobial activities of novel cobalt and zinc complexes of benzimidazole derivatives, Journal of Organometallic Chemistry, 828, 52-58.
- Kumar, B. V. S., Vaidya, S. D., Kumar, R. V., Bhirud, S. B., & Mane, R. B. (2006). Synthesis and anti-bacterial activity of some novel 2-(6-fluorochroman-2-yl)-1-alkyl/acyl/aroyl-1H-benzimidazoles. European Journal of Medicinal Chemistry, 41(5), 599-604.
- Kilcigil, G.A., & Altanlar, N. (2006). Synthesis and antifungal properties of some benzimidazole derivatives. Turkish Journal of Chemistry, 30(2), 223-228.
- Kerimov, I., Ayhan-Kilcigil, G., Can-Eke, B., Altanlar, N., & İscan, M. (2007). Synthesis, antifungal and antioxidant screening of some novel benzimidazole derivatives. Journal of Enzyme Inhibition and Medicinal Chemistry, 22(6), 696-701.
- Sharma, D., Narasimhan, B., Kumar, P., Judge, V., Narang, R., De Clercq, E., & Balzarini, J. (2009). Synthesis, antimicrobial and antiviral activity of substituted benzimidazoles. Journal of Enzyme Inhibition and Medicinal Chemistry, 24(5), 1161-1168.
- Kus, C., Ayhan-Kilcigil, G., & Eke, B. C. (2004). Synthesis and antioxidant properties of some novel benzimidazole derivatives on lipid peroxidation in the rat liver. Archives of Pharmacal Research, 27(2), 156-163.
- Kuş, C., Ayhan-Kılcıgil, G., Özbey, S., Kaynak, F. B., Kaya, M., Çoban, T., & Can-Eke, B. (2008). Synthesis and antioxidant properties of novel N-methyl-1, 3, 4-thiadiazol-2-amine and 4-methyl-2H-1,2,4-triazole-3 (4H)-thione derivatives of benzimidazole class. Bioorganic & Medicinal Chemistry, 16(8), 4294-4303.
- Buğday, N., Küçükbay, F., Apohan, E., Küçükbay, H., Serindağ, A., & Yeşilada, Ö. (2017). Synthesis and Evaluation of Novel Benzimidazole Conjugates Incorporating Amino Acids and Dipeptide Moieties. Letters in Organic Chemistry, 14, 198-206.
- [26] Shrivastava, N., Naim, M.J., Alam, M.J., Nawaz, F., Ahmed, S., & Alam, O. (2017). Benzimidazole scaffold as anticancer agent: synthetic approaches and structure– activity relationship. Archiv der Pharmazie, 350 (6), e201700040.
- [27] Gryshchenko, A.A., Tarnavskiy, S.S., Levchenko, K.V., Bdzhola, V.G., Volynets, G.P., Golub, A.G., Ruban, T.P., Vygranenko, K.V., Lukash, L.L., & Yarmoluk, S.M. (2016). Design, synthesis and biological evaluation of 5-amino-4-(1Hbenzoimidazol-2-yl)-phenyl-1, 2-dihydro-pyrrol-3-ones as inhibitors of protein kinase FGFR1. Bioorganic & Medicinal Chemistry, 24 (9), 2053-2059.
- Abdullaziz, M.A., Abdel-Mohsen, H.T., El Kerdawy, A.M., Ragab, F.A., Ali, M. M., Abu-bakr, S.M., Girgis, A.S., & El Diwani, H. I. (2017). Design, synthesis, molecular docking and cytotoxic evaluation of novel 2-furybenzimidazoles as VEGFR-2 inhibitors. European Journal of Medicinal Chemistry, 136, 315-329.
- El-Gohary, N.S., & Shaaban, M.I. (2017). Synthesis and biological evaluation of a new series of benzimidazole derivatives as antimicrobial, antiquorum-sensing and antitumor agents. European Journal of Medicinal Chemistry, 131, 255-262.
- El-Gohary, N.S. & Shaaban, M.I. (2017). Synthesis, antimicrobial, antiquorumsensing and antitumor activities of new benzimidazole analogs. European Journal of Medicinal Chemistry, 137, 439-449.
- Chojnacki, K., Wińska, P., Skierka, K., Wielechowska, M., & Bretner, M. (2017). Synthesis, in vitro antiproliferative activity and kinase profile of new benzimidazole and benzotriazole derivatives. Bioorganic Chemistry, 72, 1-10.
- Abdelgawad, M.A., Bakr, R.B., & Omar, H.A. (2017). Design, synthesis and biological evaluation of some novel benzothiazole/benzoxazole and/or benzimidazole derivatives incorporating a pyrazole scaffold as antiproliferative agents. Bioorganic Chemistry, 74, 82-90.
- Çevik, U.A., Sağlık, B.N., Korkut, B., Özkay, Y., & Ilgın, S. (2018). Antiproliferative, cytotoxic, and apoptotic effects of new benzimidazole derivatives bearing hydrazone moiety. Journal of Heterocyclic Chemistry, 55 (1), 138-148.
There are 33 citations in total.
Details
| Primary Language | Turkish |
|---|---|
| Journal Section | Articles |
| Authors | |
| Publication Date | December 31, 2022 |
| Submission Date | February 8, 2022 |
| Acceptance Date | July 1, 2022 |
| Published in Issue | Year 2022 Volume: 9 Issue: 2 |