Research Article
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Biological and computational evaluation of carbazole-based bis-thiosemicarbazones: A selective enzyme inhibition study between α-amylase and α-glucosidase

Year 2023, Volume: 53 Issue: 1, 39 - 44, 28.04.2023

Hasan Şahin Alev Arslantürk Bingül İbrahim Fazıl Şengül Murat Bingül

https://doi.org/10.26650/IstanbulJPharm.2023.1164443

Abstract

Background and Aims: Carbazole heterocyclic systems are an important class of chemicals that have been reported as valuable antidiabetic agents in the literature. Uncoincidentally, the ayurvedic antidiabetic plant Murraya koenigii Spreng (Curry tree) was the source of the first carbazole alkaloids. Another important class of chemicals in terms of antidiabetic activity is thiosemicarbazones. The hybridization of these fragments can create new potential inhibitors for α-amylase and α-glucosidase enzyme inhibitions, which is one approach controlling post-prandial hyperglycemia in type 2 diabetes patients. Methods: The four carbazole-based thiosemicarbazone compounds (4a-d) have been selected from the group library and α-amylase and α-glucosidase inhibition potencies have been evaluated. A molecular modelling study has also been carried out to provide a complementary study on how the molecules behave in terms of the enzymes’ catalytic properties.
Results: All compounds showed higher potencies than the standard acarbose in terms of α-glucosidase inhibition and very low inhibitions toward α-amylase compared to acarbose. Having the number of hydrophobic interactions determine the po- tency of the compounds was crucial with compound 4a being shown to provide the highest number of conventional H bonds and the highest percentage of inhibition values for both enzymes.
Conclusion: Carbazole-based thiosemicarbazone compounds have been found to be promising candidates in terms of both their potency and relative selectivity for developing new inhibitors that lack the usual side effects of current drugs.

Keywords

α-Amylase α-Glucosidase Carbazole Molecular Docking Thiosemicarbazones

Supporting Institution

Dicle University Scientific Research Project Department (DÜBAP)

Project Number

Eczacılık.21.002

Thanks

The authors acknowledge the Dicle University Scientific Research Project Department (DÜBAP) which supported the study’s bioassay part (Eczacılık.21.002)

References

  • Adib, M., Peytam, F., Shourgeshty, R., Mohammadi-Khanaposhtani, M., Jahani, M., Imanparast, S., . . . Mahdavi, M. (2019). Design and synthesis of new fused carbazole-imidazole derivatives as anti- diabetic agents: In vitro α-glucosidase inhibition, kinetic, and in silico studies. Bioorganic & Medicinal Chemistry Letters, 29(5), 713- 718. doi:10.1016/j.bmcl.2019.01.012
  • Antholine, W., Knight, J., Whelan, H., & Petering, D. H. (1977). Stud- ies of the reaction of 2-formylpyridine thiosemicarbazone and its iron and copper complexes with biological systems. Molecular Pharmacology, 13(1), 89-98.
  • Apostolidis, E., & Lee, C. M. (2010). In vitro potential of Ascophyl- lum nodosum phenolic antioxidant-mediated α-glucosidase and α-amylase inhibition. Journal of Food Science, 75(3), 97-102. doi:10.1111/j.1750-3841.2010.01544.x
  • Beidokhti, M. N., Eid, H. M., Villavicencio, M. L. S., Jager, A. K., Lobbens, E. S., Rasoanaivo, P. R., . . . Staerk, D. (2020). Evaluation of the anti- diabetic potential of Psidium guajava L. (Myrtaceae) using assays for alpha-glucosidase, alpha-amylase, muscle glucose uptake, liver glucose production, and triglyceride accumulation in adipocytes. J Ethnopharmacol, 257, 112877. doi:10.1016/j.jep.2020.112877
  • Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weis- sig, H., . . . Bourne, P. E. (2000). The Protein Data Bank. Nucleic Acids Res, 28(1), 235-242. doi:10.1093/nar/28.1.235
  • Bingul, M., Şenkuytu, E., Saglam, M. F., Boga, M., Kandemir, H., & Sen- gul, I. F. (2019). Synthesis, photophysical and antioxidant properties of carbazole-based bis-thiosemicarbazones. Research on Chemical Intermediates, 45(9), 4487-4499. doi:10.1007/s11164-019-03844-x
  • Biovia, D. S. (2019). Discovery Visualizer Studio v19.1.0.18287 (Ver- sion v19.1.0.18287). San Diego: Dassault Systemes.
  • Dhameja, M., & Gupta, P. (2019). Synthetic heterocyclic candi- dates as promising α-glucosidase inhibitors: An overview. Euro- pean Journal of Medicinal Chemistry, 176, 343-377. doi:10.1016/j. ejmech.2019.04.025
  • Frisch, M. J., Schlegel, H. B., Scuseria, G. E., Robb, M. A., Cheeseman, J. R., Scalmani, G., . . . Nakatsuji, H. (2009). Gaussian 09, Revision E.01. Wallingford CT.
  • Graebe, C., & Glaser, C. (1872). Ueber Carbazol. Berichte der Deutschen Chemischen Gesellschaft. 163(3), 343-360. doi. org/10.1002/jlac.18721630305
  • Iqbal, S., Khan, M. A., Javaid, K., Sadiq, R., Fazal-ur-Rehman, S., Choudhary, M. I., & Basha, F. Z. (2017). New carbazole linked 1,2,3-triazoles as highly potent non-sugar α-glucosidase inhibitors. Bioorganic Chemistry, 74, 72-81. doi:10.1016/j. bioorg.2017.07.006
  • Jakalian, A., Jack, D. B., & Bayly, C. I. (2002). Fast, efficient genera- tion of high-quality atomic charges. AM1-BCC model: II. Param- eterization and validation. J Comput Chem, 23(16), 1623-1641. doi:10.1002/jcc.10128
  • Kesari, A. N., Kesari, S., Singh, S. K., Gupta, R. K., & Watal, G. (2007). Studies on the glycemic and lipidemic effect of Murraya koenigii in experimental animals. Journal of Ethnopharmacology, 112(2), 305-311. doi:10.1016/j.jep.2007.03.023
  • Nahoum, V., Roux, G., Anton, V., Rougé, P., Puigserver, A., Bischoff, H., . . . Payan, F. (2000). Crystal structures of human pancreatic alpha-amylase in complex with carbohydrate and proteinaceous inhibitors. Biochem J, 346 Pt 1(Pt 1), 201-208.
  • Okutan, L., Kongstad, K. T., Jäger, A. K., & Staerk, D. (2014). High-res- olution α-amylase assay combined with high-performance liquid chromatography–solid-phase extraction–nuclear magnetic reso- nance spectroscopy for expedited ‘dentification of α-amylase in- hibitors: proof of concept and α-amylase inhibitor in cinnamon. Journal of Agricultural and Food Chemistry, 62(47), 11465-11471. doi:10.1021/jf5047283
  • Patel, O. P. S., Mishra, A., Maurya, R., Saini, D., Pandey, J., Taneja, I., Yadav, P. P. (2016). Naturally occurring carbazole alkaloids from Murraya koenigii as potential antidiabetic agents. Journal of Natu- ral Products, 79(5), 1276-1284. doi:10.1021/acs.jnatprod.5b00883
  • Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Green- blatt, D. M., Meng, E. C., & Ferrin, T. E. (2004). UCSF Chimera a visu- alization system for exploratory research and analysis. J Comput Chem, 25(13), 1605-1612. doi:10.1002/jcc.20084
  • Richardson, D. R. (2002). Iron chelators as therapeutic agents for the treatment of cancer. Critical Reviews in Oncology/Hematology, 42(3), 267-281. doi:10.1016/S1040-8428(01)00218-9
  • Schmidt, A. W., Reddy, K. R., & Knölker, H.-J. (2012). Occurrence, biogenesis, and synthesis of biologically active carbazole alka- loids. Chemical Reviews, 112(6), 3193-3328. doi:10.1021/cr200447s
  • Schmidt, J. S., Lauridsen, M. B., Dragsted, L. O., Nielsen, J., & Staerk, D. (2012). Development of a bioassay-coupled HPLC-SPE-ttNMR platform for identification of α-glucosidase inhibitors in apple peel (Malus × domestica Borkh.). Food Chemistry, 135(3), 1692- 1699. doi:10.1016/j.foodchem.2012.05.075
  • Shahabadi, N., Kashanian, S., & Darabi, F. (2010). DNA binding and DNA cleavage studies of a water soluble cobalt(II) complex con- taining dinitrogen Schiff base ligand: The effect of metal on the mode of binding. European Journal of Medicinal Chemistry, 45(9), 4239-4245. doi:10.1016/j.ejmech.2010.06.020
  • Shehzad, M. T., Imran, A., Njateng, G. S. S., Hameed, A., Islam, M., al-Rashida, M., . . . Iqbal, J. (2019). Benzoxazinone-thiosemicarba- zones as antidiabetic leads via aldose reductase inhibition: Syn- thesis, biological screening and molecular docking study. Bioor- ganic Chemistry, 87, 857-866. doi:10.1016/j.bioorg.2018.12.006
  • Shehzad, M. T., Khan, A., Halim, S. A., Hameed, A., Imran, A., Iqbal, J., ... Al-Harrasi, A. (2021). Synthesis of indole-substituted thiosemi- carbazones as an aldose reductase inhibitor: an in vitro, selectivity and in silico study. Future Medicinal Chemistry, 13(14), 1185-1201. doi:10.4155/fmc-2020-0060
  • Tagami, T., Yamashita, K., Okuyama, M., Mori, H., Yao, M., & Kimura, A. (2013). Molecular basis for the recognition of long-chain sub- strates by plant α-glucosidases. J Biol Chem, 288(26), 19296-19303. doi:10.1074/jbc.M113.465211
  • Tan, M. A., Sharma, N., & An, S. S. A. (2022). Phyto-carbazole al- kaloids from the Rutaceae Family as potential protective agents against neurodegenerative diseases. Antioxidants, 11(3), 493. Re- trieved from https://www.mdpi.com/2076-3921/11/3/493
  • Tok, F., Küçükal, B., Baltaş, N., Tatar Yılmaz, G., & Koçyiğit- Kaymakçıoğlu, B. (2022). Synthesis of novel thiosemicarbazone derivatives as antidiabetic agent with enzyme kinetic studies and antioxidant activity. Phosphorus, Sulfur, and Silicon and the Related Elements, 1-11. doi:10.1080/10426507.2022.2099857

Year 2023, Volume: 53 Issue: 1, 39 - 44, 28.04.2023

Hasan Şahin Alev Arslantürk Bingül İbrahim Fazıl Şengül Murat Bingül

https://doi.org/10.26650/IstanbulJPharm.2023.1164443

Abstract

Project Number

Eczacılık.21.002

References

  • Adib, M., Peytam, F., Shourgeshty, R., Mohammadi-Khanaposhtani, M., Jahani, M., Imanparast, S., . . . Mahdavi, M. (2019). Design and synthesis of new fused carbazole-imidazole derivatives as anti- diabetic agents: In vitro α-glucosidase inhibition, kinetic, and in silico studies. Bioorganic & Medicinal Chemistry Letters, 29(5), 713- 718. doi:10.1016/j.bmcl.2019.01.012
  • Antholine, W., Knight, J., Whelan, H., & Petering, D. H. (1977). Stud- ies of the reaction of 2-formylpyridine thiosemicarbazone and its iron and copper complexes with biological systems. Molecular Pharmacology, 13(1), 89-98.
  • Apostolidis, E., & Lee, C. M. (2010). In vitro potential of Ascophyl- lum nodosum phenolic antioxidant-mediated α-glucosidase and α-amylase inhibition. Journal of Food Science, 75(3), 97-102. doi:10.1111/j.1750-3841.2010.01544.x
  • Beidokhti, M. N., Eid, H. M., Villavicencio, M. L. S., Jager, A. K., Lobbens, E. S., Rasoanaivo, P. R., . . . Staerk, D. (2020). Evaluation of the anti- diabetic potential of Psidium guajava L. (Myrtaceae) using assays for alpha-glucosidase, alpha-amylase, muscle glucose uptake, liver glucose production, and triglyceride accumulation in adipocytes. J Ethnopharmacol, 257, 112877. doi:10.1016/j.jep.2020.112877
  • Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weis- sig, H., . . . Bourne, P. E. (2000). The Protein Data Bank. Nucleic Acids Res, 28(1), 235-242. doi:10.1093/nar/28.1.235
  • Bingul, M., Şenkuytu, E., Saglam, M. F., Boga, M., Kandemir, H., & Sen- gul, I. F. (2019). Synthesis, photophysical and antioxidant properties of carbazole-based bis-thiosemicarbazones. Research on Chemical Intermediates, 45(9), 4487-4499. doi:10.1007/s11164-019-03844-x
  • Biovia, D. S. (2019). Discovery Visualizer Studio v19.1.0.18287 (Ver- sion v19.1.0.18287). San Diego: Dassault Systemes.
  • Dhameja, M., & Gupta, P. (2019). Synthetic heterocyclic candi- dates as promising α-glucosidase inhibitors: An overview. Euro- pean Journal of Medicinal Chemistry, 176, 343-377. doi:10.1016/j. ejmech.2019.04.025
  • Frisch, M. J., Schlegel, H. B., Scuseria, G. E., Robb, M. A., Cheeseman, J. R., Scalmani, G., . . . Nakatsuji, H. (2009). Gaussian 09, Revision E.01. Wallingford CT.
  • Graebe, C., & Glaser, C. (1872). Ueber Carbazol. Berichte der Deutschen Chemischen Gesellschaft. 163(3), 343-360. doi. org/10.1002/jlac.18721630305
  • Iqbal, S., Khan, M. A., Javaid, K., Sadiq, R., Fazal-ur-Rehman, S., Choudhary, M. I., & Basha, F. Z. (2017). New carbazole linked 1,2,3-triazoles as highly potent non-sugar α-glucosidase inhibitors. Bioorganic Chemistry, 74, 72-81. doi:10.1016/j. bioorg.2017.07.006
  • Jakalian, A., Jack, D. B., & Bayly, C. I. (2002). Fast, efficient genera- tion of high-quality atomic charges. AM1-BCC model: II. Param- eterization and validation. J Comput Chem, 23(16), 1623-1641. doi:10.1002/jcc.10128
  • Kesari, A. N., Kesari, S., Singh, S. K., Gupta, R. K., & Watal, G. (2007). Studies on the glycemic and lipidemic effect of Murraya koenigii in experimental animals. Journal of Ethnopharmacology, 112(2), 305-311. doi:10.1016/j.jep.2007.03.023
  • Nahoum, V., Roux, G., Anton, V., Rougé, P., Puigserver, A., Bischoff, H., . . . Payan, F. (2000). Crystal structures of human pancreatic alpha-amylase in complex with carbohydrate and proteinaceous inhibitors. Biochem J, 346 Pt 1(Pt 1), 201-208.
  • Okutan, L., Kongstad, K. T., Jäger, A. K., & Staerk, D. (2014). High-res- olution α-amylase assay combined with high-performance liquid chromatography–solid-phase extraction–nuclear magnetic reso- nance spectroscopy for expedited ‘dentification of α-amylase in- hibitors: proof of concept and α-amylase inhibitor in cinnamon. Journal of Agricultural and Food Chemistry, 62(47), 11465-11471. doi:10.1021/jf5047283
  • Patel, O. P. S., Mishra, A., Maurya, R., Saini, D., Pandey, J., Taneja, I., Yadav, P. P. (2016). Naturally occurring carbazole alkaloids from Murraya koenigii as potential antidiabetic agents. Journal of Natu- ral Products, 79(5), 1276-1284. doi:10.1021/acs.jnatprod.5b00883
  • Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Green- blatt, D. M., Meng, E. C., & Ferrin, T. E. (2004). UCSF Chimera a visu- alization system for exploratory research and analysis. J Comput Chem, 25(13), 1605-1612. doi:10.1002/jcc.20084
  • Richardson, D. R. (2002). Iron chelators as therapeutic agents for the treatment of cancer. Critical Reviews in Oncology/Hematology, 42(3), 267-281. doi:10.1016/S1040-8428(01)00218-9
  • Schmidt, A. W., Reddy, K. R., & Knölker, H.-J. (2012). Occurrence, biogenesis, and synthesis of biologically active carbazole alka- loids. Chemical Reviews, 112(6), 3193-3328. doi:10.1021/cr200447s
  • Schmidt, J. S., Lauridsen, M. B., Dragsted, L. O., Nielsen, J., & Staerk, D. (2012). Development of a bioassay-coupled HPLC-SPE-ttNMR platform for identification of α-glucosidase inhibitors in apple peel (Malus × domestica Borkh.). Food Chemistry, 135(3), 1692- 1699. doi:10.1016/j.foodchem.2012.05.075
  • Shahabadi, N., Kashanian, S., & Darabi, F. (2010). DNA binding and DNA cleavage studies of a water soluble cobalt(II) complex con- taining dinitrogen Schiff base ligand: The effect of metal on the mode of binding. European Journal of Medicinal Chemistry, 45(9), 4239-4245. doi:10.1016/j.ejmech.2010.06.020
  • Shehzad, M. T., Imran, A., Njateng, G. S. S., Hameed, A., Islam, M., al-Rashida, M., . . . Iqbal, J. (2019). Benzoxazinone-thiosemicarba- zones as antidiabetic leads via aldose reductase inhibition: Syn- thesis, biological screening and molecular docking study. Bioor- ganic Chemistry, 87, 857-866. doi:10.1016/j.bioorg.2018.12.006
  • Shehzad, M. T., Khan, A., Halim, S. A., Hameed, A., Imran, A., Iqbal, J., ... Al-Harrasi, A. (2021). Synthesis of indole-substituted thiosemi- carbazones as an aldose reductase inhibitor: an in vitro, selectivity and in silico study. Future Medicinal Chemistry, 13(14), 1185-1201. doi:10.4155/fmc-2020-0060
  • Tagami, T., Yamashita, K., Okuyama, M., Mori, H., Yao, M., & Kimura, A. (2013). Molecular basis for the recognition of long-chain sub- strates by plant α-glucosidases. J Biol Chem, 288(26), 19296-19303. doi:10.1074/jbc.M113.465211
  • Tan, M. A., Sharma, N., & An, S. S. A. (2022). Phyto-carbazole al- kaloids from the Rutaceae Family as potential protective agents against neurodegenerative diseases. Antioxidants, 11(3), 493. Re- trieved from https://www.mdpi.com/2076-3921/11/3/493
  • Tok, F., Küçükal, B., Baltaş, N., Tatar Yılmaz, G., & Koçyiğit- Kaymakçıoğlu, B. (2022). Synthesis of novel thiosemicarbazone derivatives as antidiabetic agent with enzyme kinetic studies and antioxidant activity. Phosphorus, Sulfur, and Silicon and the Related Elements, 1-11. doi:10.1080/10426507.2022.2099857
There are 26 citations in total.

Details

Primary Language English
Subjects Pharmacology and Pharmaceutical Sciences
Journal Section Original Article
Authors

Hasan Şahin 0000-0002-8325-8116

Alev Arslantürk Bingül This is me 0000-0003-0744-0968

İbrahim Fazıl Şengül 0000-0001-9386-4892

Murat Bingül 0000-0002-3909-0694

Project Number Eczacılık.21.002
Publication Date April 28, 2023
Submission Date August 19, 2022
Published in Issue Year 2023 Volume: 53 Issue: 1

Cite

APA Şahin, H., Arslantürk Bingül, A., Şengül, İ. F., Bingül, M. (2023). Biological and computational evaluation of carbazole-based bis-thiosemicarbazones: A selective enzyme inhibition study between α-amylase and α-glucosidase. İstanbul Journal of Pharmacy, 53(1), 39-44. https://doi.org/10.26650/IstanbulJPharm.2023.1164443
AMA Şahin H, Arslantürk Bingül A, Şengül İF, Bingül M. Biological and computational evaluation of carbazole-based bis-thiosemicarbazones: A selective enzyme inhibition study between α-amylase and α-glucosidase. iujp. April 2023;53(1):39-44. doi:10.26650/IstanbulJPharm.2023.1164443
Chicago Şahin, Hasan, Alev Arslantürk Bingül, İbrahim Fazıl Şengül, and Murat Bingül. “Biological and Computational Evaluation of Carbazole-Based Bis-Thiosemicarbazones: A Selective Enzyme Inhibition Study Between α-Amylase and α-Glucosidase”. İstanbul Journal of Pharmacy 53, no. 1 (April 2023): 39-44. https://doi.org/10.26650/IstanbulJPharm.2023.1164443.
EndNote Şahin H, Arslantürk Bingül A, Şengül İF, Bingül M (April 1, 2023) Biological and computational evaluation of carbazole-based bis-thiosemicarbazones: A selective enzyme inhibition study between α-amylase and α-glucosidase. İstanbul Journal of Pharmacy 53 1 39–44.
IEEE H. Şahin, A. Arslantürk Bingül, İ. F. Şengül, and M. Bingül, “Biological and computational evaluation of carbazole-based bis-thiosemicarbazones: A selective enzyme inhibition study between α-amylase and α-glucosidase”, iujp, vol. 53, no. 1, pp. 39–44, 2023, doi: 10.26650/IstanbulJPharm.2023.1164443.
ISNAD Şahin, Hasan et al. “Biological and Computational Evaluation of Carbazole-Based Bis-Thiosemicarbazones: A Selective Enzyme Inhibition Study Between α-Amylase and α-Glucosidase”. İstanbul Journal of Pharmacy 53/1 (April 2023), 39-44. https://doi.org/10.26650/IstanbulJPharm.2023.1164443.
JAMA Şahin H, Arslantürk Bingül A, Şengül İF, Bingül M. Biological and computational evaluation of carbazole-based bis-thiosemicarbazones: A selective enzyme inhibition study between α-amylase and α-glucosidase. iujp. 2023;53:39–44.
MLA Şahin, Hasan et al. “Biological and Computational Evaluation of Carbazole-Based Bis-Thiosemicarbazones: A Selective Enzyme Inhibition Study Between α-Amylase and α-Glucosidase”. İstanbul Journal of Pharmacy, vol. 53, no. 1, 2023, pp. 39-44, doi:10.26650/IstanbulJPharm.2023.1164443.
Vancouver Şahin H, Arslantürk Bingül A, Şengül İF, Bingül M. Biological and computational evaluation of carbazole-based bis-thiosemicarbazones: A selective enzyme inhibition study between α-amylase and α-glucosidase. iujp. 2023;53(1):39-44.
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