Exploring the Antibacterial and Enzyme Inhibitory Potential of Selected β-Carboline Derivatives: In Vitro and In Silico Insights

Abstract

β-Carboline derivatives have a wide range of biological effects such as antiviral, antitumor and antimalarial and are therefore important compounds for drug development. In this study, the effect of some β-carboline derivatives on glucose 6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), and antibacterial activities were investigated. For this purpose, affinity chromatography was used to separate G6PD and 6PGD from human erythrocytes with a specific activity of 1.96 EU/ml protein and 4.569 EU/ml protein, respectively and then in vitro effects of compounds were assayed. It was found that only 1-Isopropyl-2,3,4,9-tetrahydro-1H-beta-carboline, among the selected β-Carboline derivatives, inhibited G6PD with an IC50 value of 31.2 µM. It was determined that other derivatives did not have any effect on G6PD and 6PGD activities. Besides antibacterial effects of compounds were examined and compounds were found effective against Escherichia coli, Klebsiella pneumoniae, and Acinetobacter haemolyticus. Molecular docking study of isopropyl-2,3,4,9-tetrahydro-1H-beta-carboline molecule to the hG6PD (6E08) receptor was performed and the estimated binding energy was determined as -6.97 kcal/mol. According to the results of antibacterial studies, compounds were docked into some specific proteins of microorganisms as well and possible interactions between receptors and derivatives were discussed.

Keywords

• 6-phosphogluconate dehydrogenase
• Antibacterial
• structure-activity relationship
• glucose 6-phosphate dehydrogenase
• molecular docking

References

1. 1. Hesse M. Alkaloids: Nature’s Curse or Blessing; Wiley-VCH: Zürich, Switzerland, 2002; pp. 14–27.
2. 2. Laine, A.E.; Lood, C.; Koskinen, A.M. Molecules. 2014, 19(2),1544-1567.
3. 3. Saxton, J.E. Monoterpenoid Indole Alkaloids: Supplement to Part. 4.; Wiley: Chichester, UK,1994;162–176, 719–725.
4. 4. Davis, R.A.; Duffy, S.; Avery, V.M.; Camp, D.; Hooper, J.N. Tetrahedron Lett. 2010, 51(4),583-585.
5. 5. Chan, S.T.; Pearce, A.N.; Page, M.J.; Kaiser, M.; Copp, B.R. J Nat Prod. 2011, 74(9),1972-1979.
6. 6. Gellis, A.; Dumètre, A.; Hutter, S.; Ollivier, E.; Vanelle, P.; Azas, N. Biomed Pharmacother. 2012, 66(5),339-347.
7. 7. Ashok, P.; Ganguly, S.; Murugesan, S. Drug Discov. Today. 2014, 19(11),1781-1791.
8. 8. Azas, N.; Laurencin, N.; Delmas, F.; Di Giorgio, C.; Gasquet, M.; Laget, M.; et al. Parasitol Res. 2002, 88, 165–71.

9. 9. Fiot, J.; Sanon, S.; Azas, N.; Mahiou, V.; Jansen, O.; Angenot, L.; et al. J Ethnopharmacol. 2006, 106, 173–8.
10. 10. Daugan, A.; Grondin, P.; Ruault, C.; le Monnier, D.G.; Coste, H.; Kirilovsky, J.; Hyafil, F.; Labaudiniere, R. J. Med. Chem. 2003, 46, 4525–4532.
11. 11. Davis, R.A.; Duffy, S.; Avery, V.M.; Camp, D.; Hooper, J.N.A. Tetrahedron Lett. 2010, 51, 583–585.
12. 12. Chan, S.T.S.; Pearce, A.N.; Page, M.J.; Kaiser, M.; Copp, B.R. J. Nat. Prod. 2011, 74, 1972–1979.
13. 13. Gellis, A.; Dumètre, A.; Lanzada, G.; Hutter, S.; Ollivier, E.; Vanelle, P.; Azas, N. Biomed. Pharmacother. 2012, 66, 339–347.
14. 14. Van Maarseveen, J.H.; Hermkens, P.H.H.; de Clercq, E.; Balzarini, J.; Scheeren, H.W.; Kruse, C.G. J. Med. Chem. 1992, 35, 3223–3230.
15. 15. Miller, J.F.; Turner, E.M.; Sherrill, R.G.; Gudmundsson, K.; Spaltenstein, A.; Sethna, P.; Brown, K.W.; Harvey, R.; Romines, K.R.; Golden, P. Bioorg. Med. Chem. Lett. 2010, 20, 256–259.
16. 16. Shen, Y.; Chang, Y.; Lin, C.; Liaw, C.; Kuo, Y.H.; Tu, L.; Yeh, S.F.; Chern, J. Mar. Drugs. 2011, 9, 256–277.
17. 17. Skouta, R.; Hayano, M.; Shimada, K.; Stockwell, B.R. Bioorg. Med. Chem. Lett. 2012, 22, 5707–5713.
18. 18. Hotha, S.; Yarrow, J.C.; Yang, J.G.; Garrett, S.; Renduchintala, K.V.; Mayer, T.U.; Kapoor, T.M. Angew. Chem. 2003, 115, 2481–2484.
19. 19. Serafini, P.; Meckel, K.; Kelso, M.; Noonan, K.; Califano, J.; Koch, W.; Dolcetti, L.; Bronte, V.; Borrello, I. J. Exp. Med. 2006, 203, 2691–2702.
20. 20. Wamelink, M.; Struys, E.; Jakobs, C. JIMD: Official Journal of the Society for the Study of Inborn Errors of Metabolism. 2008, 31(6), 703-717.
21. 21. del Campo, J.S.M.; Patiño, R. Thermochim. Acta. 2011, 517(1-2), 40-44. 22. Kaplan, M.; Hammerman. Paper presented at the Seminars in Fetal and Neonatal Medicine. 2010.
22. 23. Ulusu, N.N.; Kus, M.S.; Acan, N.L.; Tezcan, E.F. IJBCB. 1999, 31(7), 787-796.
23. 24. Winiarska, K.; Węgrzynowicz, M.; Jagielski, A.K.; Bryła, J. Metabolism, 2003, 52(6), 739-746.
24. 25. Riganti, C.; Gazzano, E.; Polimeni, M.; Aldieri, E.; Ghigo, D. Free Radic Biol Med. 2012, 53(3), 421-436.
25. 26. Tsouko, E.; Khan, A.S.; White, M.A.; Han, J.J.; Shi, Y.; Merchant, F.A.; ... & Frigo, D.E. Oncogenesis. 2014, 3(5), e103-e103.
26. 27. Furukawa, T.; Tabata, S.; Minami, K.; Yamamoto, M.; Kawahara, K.; Tanimoto, A. BBA-Gen Subjects. 2023, 1867(3), 130301.
27. 28. Atamna, H.; Pascarmona, G.; Ginsburg, H. Mol Biochem Parasit, 1994, 67(1), 79-89.
28. 29. López, C.; Saravia, C.; Gomez, A.; Hoebeke, J.; Patarroyo, M.A. Gene. 2010, 467(1-2), 1-12.
29. 30. Wolach, B.; Ashkenazi, M.; Grossmann, R.; Gavrieli, R.; Friedman, Z.; Bashan, N. Pediatr Res. 2004, 55, 807–813.
30. 31. Elyassi, A.R.; Rowshan, H.H. Anesth Prog. 2009, 56, 86–91.
31. 32. Wu, Y.H.; Tseng, C.P.; Cheng, M.L.; Ho, H.Y.; Shih, S.R.; Chiu, D.T. J Infect Dis. 2008, 197, 812–816.
32. 33. Ninfali, P.; Orsenigo, I.; Baronciani, L.; Rapa, S. Prep Biochem. 1990, 20(3-4), 297-309.
33. 34. Adem, S.; Ciftci, M. Protein Expres Purif. 2012, 81(1), 1-4.
34. 35. Akkemik, E.; Budak, H.; Ciftci, M. J Enzym Inhıb Med Ch. 2010, 25(6), 871-875.
35. 36. Morelli, A.; Benatti, U.; Gaetani, G.; De Flora, A. Proceedings of the National Academy of Sciences, 1978, 75(4), 1979-1983.
36. 37. Beutler, E. Red cell metabolism. A manual of biochemical methods, 1975, 11-12.
37. 38. Akkemik, E.; Budak, H.; Ciftci, M. J Enzym Inhıb Med Ch. 2010, 25(4), 476-479.
38. 39. Mancuso, G.; Midiri, A.; Gerace, E.; Biondo, C. Pathogens 2021, 10(10), 1310.
39. 40. Kowalska-Krochmal, B.; Dudek-Wicher, R. Pathogens. 2021, 10(2), 165.
40. 41. Wiegand, I.; Hilpert, K.; Hancock, R.E.W. Nat. Protoc3. 2008, 163–175.
41. 42. Denev, P.; Kratchanova, M.; Ciz, M.; Lojek, A.; Vasicek, O.; Nedelcheva, P.; … Vojtek, L. Food Chem. 2014, 157, 37-44.
42. 43. CLSI, Clinical and Laboratory Standards Institute, CLSI Document no. M07, 2018. 11th ed., Wayne, Clinical and Laboratory Standards Institute.
43. 44. National Committee for Clinical Laboratory Standard, 1999.
44. 45. Trott, O.; Olson, A.J. J Comput Chem. 2010, 31(2), 455-461.
45. 46. Hwang, S.; Mruk, K.; Rahighi, S.; Raub, A.G.; Chen, C.H.; Dorn, L.E.; et al. Nat Commun. 2018, 9(1), 1-12.
46. 47. Mouilleron, S.; Badet-Denisot, M.A.; Golinelli-Pimpaneau, B. J Mol Biol. 2008, 377(4), 1174-1185.
47. 48. Caprari, S.; Brandi, V.; Pasquadibisceglie, A.; Polticelli, F. J. Biomol. Struct. Dyn. 2020, 38(15), 4508-4520.
48. 49. Stogios, P.J.; Kuhn, M.L.; Evdokimova, E.; Law, M.; Courvalin, P.; Savchenko, A. ACS Infect. Dis. 2017, 3(2), 132-143.
49. 50 Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Adv Drug Delıver Rev. 1997, 23(1-3), 3-25.
50. 51. T. Martin. User’s guide for TEST (version4.2) (Toxicity Estimation Software Tool): a program to estimate toxicity from molecular structure. EPA/600/R-16/058.
51. 52. Ramírez-Nava, E.J.; Hernández-Ochoa, B.; Navarrete-Vázquez, G.; Arreguín-Espinosa, R.; Ortega-Cuellar, D.; González-Valdez, A.; ... & Gómez-Manzo, S. BBA-Gen Subjects. 2021, 1865(3), 129828.
52. 53. Konaté, K.; Mavoungou, J.F.; Lepengué, A.N.; Aworet-Samseny, R.R.; Hilou, A.; Souza, A.; ... M’Batchi, B. Ann Clin Microb Anti, 2012, 11, 1-12.
53. 54. Venkateswarulu, T.C.; Srirama, K.; Mikkili, I.; Dulla, J.B.; Alugunulla, V.N.; Sweety, D.; Karlapudi, A.P. Karbala Int. J. Mod. Sci. 2019, 5(4), 8.
54. 55. Berche, P.; Gaillard, J.L.; Simonet, M. Nosocomial Infections Caused by Bacteria and Their Prevention in Bacteriology. Ed Flammarion Medicine Sciences 1988, 64–71.
55. 56. Khan, M.A.; Göpel, Y.; Milewski, S.; Görke, B. Front Microbiol, 2016, 7, 208452.
56. 57. Begley, D.J.; Brightman, M.W. Basel: Birkhäuser Basel 2003, 39–78.
57. 58. Daina, A.; Zoete, V. ChemMedChem. 2016, 11(11), 1117-1121.
58. 59. Daina, A.; Michielin, O.; Zoete, V. Epub ahead of print. 2017.
59. 60. Selick, H.E.; Beresford, A.P.; Tarbit, M.H. Drug Discov. Today. 2002, 7, 109–116.
60. 61. Yenigun, S.; Basar, Y.; Gül, F.; Ipek, Y.; Gok, M.; Behcet, L.; ... & Demirtas, I. ChemistrySelect, 2024, 9(18), e202400919.
61. 62. Yenigun, S.; Basar, Y.; Ipek, Y.; Behcet, L.; Demirtas, I.; Ozen, T. J. Biol. Act. Prod. Nat, 2024, 14(3), 286-315.
62. 63. Yenigun, S.; Basar, Y.; Ipek, Y.; Gok, M.; Behcet, L.; Ozen, T.; Demirtas, I. Process Biochemistry, 2024, 143, 234-247.
63. 64. Chi, G. F.; Khan, S.; Başar, Y.; Kuete, J. R.; Matieta, V. Y.; Kuete, J. B.; ... & Shaheen, F. S. Afr. J. Bot., 2025, 180, 96-106.
64. 65. Yenigun, S.; Basar, Y.; Gul, F.; Marah, S.; Behcet, L.; Demirtas, I.; Ozen, T. ChemistrySelect, 2024, 9(18), e202400583.
65. 66. Başar, Y.; Yenigün, S.; Gül, F.; Ozen, T.; Demirtas, İ.; Alma, M. H.; Temel, S. IJCT, 2024, 8(1), 62-71.
66. 67. Burden, N.; Creton, S.; Weltje, L.; et al. Regul. Toxicol. Pharmacol., 2014, 70: 442–445.
67. 68. Griffiths, A.J; Miller, J.H; Suzuki, D.T; et al. In: Freeman WH (ed) An Introduction to Genetic Analysis. 2000.