Skip to main content
SpringerLink
Log in

Bisbenzimidazole salts and their in silico–in vitro inhibitory abilities on hCA I, hCA II, and AChE enzymes

  • Original Paper
  • Published:
Monatshefte für Chemie - Chemical Monthly Aims and scope Submit manuscript

Abstract

Eight new bisbenzimidazolium halides were prepared from alkyl halides and 4,4′-bis[(benzimidazol-1-yl)methyl]-1,1′-biphenyl.The structures of the benzimidazole salts were characterized using elemental analysis techniques as well as 1H, 13C NMR, and FT-IR spectroscopic methods. The inhibitory effects of the benzimidazole derivatives were measured against human carbonic anhydrase I (hCA I), human carbonic anhydrase II (hCA II), and acetylcholinesterase (AChE) enzymes. All benzimidazolium halides exhibited significant enzyme inhibitory properties. They showed highly potent inhibitory effect on AChE and hCAs (Ki values are in the range of 15.7 ± 0.8 to 49.7 ± 10.1 nM, 14.6 ± 1.5 to 70.7 ± 2.7 nM, and 17.4 ± 2.8 to 38 ± 10 nM for AChE, hCA I, and hCA II, respectively). The binding orientation of the synthesized bisbenzimidazolium halides was evaluated by molecular docking studies, reflecting the importance of the p-methylbenzyl, m-methylbenzyl, p-nitrophenethyl, and 3-(1,3-dioxoisoindolin-2-yl)methyl) groups in protein–ligand interaction. The docking results support the Ki values of the respective compounds in this study. The structure–activity relationships against the various targets are clearly shown in three dimensions at the atomic level by their interactions with the mentioned enzymes.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

Data regarding the article can be accessed from the Supplementary information file at https://doi.org/10.1007/s00706-024-03204-5.

References

  1. Brishty SR, Hossain MdJ, Khandaker MU, Faruque MRI, Osman H, Abdur Rahman SM (2021) Front Pharm 12:762807

    CAS  Google Scholar 

  2. Barot KP, Nikolova S, Ivanov I, Ghate MD (2013) Mini Rev Med Chem 13:1421

    CAS  PubMed  Google Scholar 

  3. Küçükbay H, Yılmaz Ü, Şireci N, Güvenç AN (2011) Turk J Chem 35:561

    Google Scholar 

  4. Patil PO, Bari SB (2014) Arab J Chem 7:857

    CAS  Google Scholar 

  5. Atmaca H, İlhan S, Batır MB, Pulat ÇÇ, Güner A, Bektaş H (2020) Chem Biol Interact 327:109163

    CAS  PubMed  Google Scholar 

  6. Bansal Y, Silakari O (2012) Bioorg Med Chem 20:6208

    CAS  PubMed  Google Scholar 

  7. Tonelli M, Simone M, Tasso B, Novelli F, Boido V, Sparatore F, Paglietti G, Pricl S, Giliberti G, Blois S, Ibba C (2010) Bioorg Med Chem 18:2937

    CAS  PubMed  Google Scholar 

  8. Menteşe E, Yılmaz F, Emirik M, Ülker S, Kahveci B (2018) Bioorg Chem 76:478

    PubMed  Google Scholar 

  9. Kus C, Ayhan-Kilcigil G, Eke BC (2004) Arch Pharm Res 27:156

    CAS  PubMed  Google Scholar 

  10. Abdel-Motaal M, Almohawes K, Tantawy MA (2020) Bioorg Chem 101:103972

    CAS  PubMed  Google Scholar 

  11. Çağlayan C, Taslimi P, Demir Y, Küçükler S, Kandemir FM, Gulcin I (2019) J Biochem Mol Toxicol 33:e22381

    PubMed  Google Scholar 

  12. Kalaycı M, Türkeş C, Arslan M, Demir Y, Beydemir Ş (2021) Arch Pharm 354:e2000282

    Google Scholar 

  13. Caglayan C, Taslimi P, Türk C, Gulcin İ, Kandemir FM, Demir Y, Beydemir Ş (2020) Environ Sci Pollut Res 27:10607

    CAS  Google Scholar 

  14. Sever B, Türkeş C, Altıntop MD, Demir Y, Beydemir Ş (2020) Int J Biol Macromol 163:1970

    CAS  PubMed  Google Scholar 

  15. Askin S, Tahtaci H, Türkeş C, Demir Y, Ece A, Çiftçi GA, Beydemir Ş (2021) Bioorg Chem 113:105009

    CAS  PubMed  Google Scholar 

  16. Hou Z, Li C, Liu Y, Zhang M, Wang Y, Fan Z, Guo C, Lin B, Liu Y (2020) J Enzyme Inhib Med Chem 35:383

    CAS  PubMed  Google Scholar 

  17. Hoff E, Zou D, Schiza S, Demir Y, Grote L, Bouloukaki I, Hedner J (2020) J Sleep Res 29:e12956

    PubMed  Google Scholar 

  18. Yamali C, Gul HI, Cakir T, Demir Y, Gulcin I (2020) Lett Drug Des Discov 17:1283

    CAS  Google Scholar 

  19. Cakmak O, Ökten S, Alımlı D, Ersanlı CC, Taslimi P, Koçyiğit ÜM (2020) J Mol Struct 1220:128666

    CAS  Google Scholar 

  20. Aydin BO, Anil D, Demir Y (2021) Arch Pharm 354:2000330

    CAS  Google Scholar 

  21. Tugrak M, Gul HI, Demir Y, Gulcin I (2021) Arch Pharm 354:2000230

    CAS  Google Scholar 

  22. Sever B, Türkeş C, Altıntop MD, Demir Y, Akalın Çiftçi G, Beydemir Ş (2021) Arch Pharm 354:2100294

    CAS  Google Scholar 

  23. Osmaniye D, Türkeş C, Demir Y, Özkay Y, Beydemir Ş, Kaplancıklı ZA (2022) Arch Pharm 355:e2200132

    Google Scholar 

  24. Kaya Y, Erçağ A, Zorlu Y, Demir Y, Gülçin İ (2022) J Biol Inorg Chem 27:271

    CAS  PubMed  Google Scholar 

  25. Innocenti A, Ozturk Sarikaya SB, Gulcin I, Supuran CT (2010) Bioorg Med Chem 18:2159

    CAS  PubMed  Google Scholar 

  26. Türkan F, Huyut Z, Demir Y, Ertaş F, Beydemir Ş (2019) Arch Physiol Biochem 125:235

    PubMed  Google Scholar 

  27. Bilginer S, Anıl B, Koca M, Demir Y, Gülçin İ (2021) Turk J Chem 45:805

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Mahmudov I, Demir Y, Sert Y, Abdullayev Y, Sujayev A, Alwasel SH, Gulcin I (2022) Arab J Chem 15:103645

    CAS  Google Scholar 

  29. Maharramov A, Kurbanova M, Taslimi P, Demir Y, Safarova A, Huseyinov E, Gulcin İ (2021) Org Commun 14:144

    CAS  Google Scholar 

  30. Tugrak M, Gul HI, Demir Y, Levent S, Gulcin I (2021) Arch Pharm 354:2000375

    CAS  Google Scholar 

  31. Manach C, Scalbert A, Morand C, Jimenez L (2004) Am J Clin Nutrit 79:727

    CAS  PubMed  Google Scholar 

  32. Ellis J (2005) Am Osteopth Assoc 105:145

    Google Scholar 

  33. Colovic MB, Krstic DZ, Lazarevic-Pasti TD, Bondžić AM, Vasić VM (2013) Curr Neuropharmacol 11:315

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Akıncıoğlu A, Akıncıoğlu H, Gülçin İ, Durdagi S, Supuran CT, Göksu S (2015) Bioorg Med Chem 23:3592

    PubMed  Google Scholar 

  35. Akıncıoğlu A, Topal M, Gülçin İ, Göksu S (2014) Arch Pharm 347:68

    Google Scholar 

  36. Wang L, Moraleda I, Iriepa I, Romera A, Lopez-Munoz F, Chioua M, Inokuchi T, Bartolini M, Marco-Contelles J (2017) Medchemcomm 8:1307

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Gul Hİ, Yazici Z, Tanc M, Supuran CT (2016) J Enzyme Inhib Med Chem 31:1540

    CAS  PubMed  Google Scholar 

  38. Kazancı A, Gök Y, Kaya R, Aktaş A, Taslimi P, Gülçin İ (2021) Polyhedron 193:114866

    Google Scholar 

  39. Saadiq M, Uddin G, Latif A, Ali M, Akbar N, Ammara AS, Ahmad M, Zahoor M, Khan A (2022) ACS Omega 7:705

    CAS  PubMed  Google Scholar 

  40. Yılmaz Ü, Şireci N, Deniz S, Küçükbay H (2010) Appl Organomet Chem 24:414

    Google Scholar 

  41. Zengin R, Gök Y, Demir Y, Şen B, Taskin-Tok T, Aktaş A, Demirci Ö, Gülçin İ, Aygün M (2023) J Fluorine Chem 267:110094

    CAS  Google Scholar 

  42. Hsiao S-H, Teng C-Y, Kung Y-R (2015) RSC Adv 5:93591

    CAS  Google Scholar 

  43. Smith BC (2020) Spectroscopy 35:26

    CAS  Google Scholar 

  44. Ökten S, Aydın A, Koçyiğit ÜM, Çakmak O, Erkan S, Andac CA, Taslimi P, Gülçin İ (2020) Arch Pharm 3553:e2000086

    Google Scholar 

  45. Ellman GL, Courtney KD, Andres V Jr (1961) Biochem Pharm 7:88

    CAS  PubMed  Google Scholar 

  46. Erdemir F, Celepci DB, Aktaş A, Gök Y, Kaya R, Taslimi P, Demir Y, Gulçin İ (2019) Bioorg Chem 91:103134

    CAS  PubMed  Google Scholar 

  47. Erdoğan M, Polat Köse L, Eşsiz S, Gülçin İ (2021) Arch Pharm 354:e2100113

    Google Scholar 

  48. Hashmi S, Khan S, Shafiq Z, Taslimi P, Ishaq M, Sadeghian N, Karaman HS, Akhtar N, Islam M, Asari A, Mohamad H, Gulçin İ (2021) Bioorg Chem 107:104554

    CAS  PubMed  Google Scholar 

  49. Burmaoglu S, Yilmaz AO, Polat MF, Kaya R, Gulcin İ, Algul O (2021) Arch Physiol Biochem 127:15

    Google Scholar 

  50. Verpoorte JA, Mehta S, Edsall JT (1967) J Biol Chem 242:4221

    CAS  PubMed  Google Scholar 

  51. Efeoglu C, Selcuk O, Demir B, Sahin E, Sari H, Türkeş C, Demir Y, Nural Y, Beydemir Ş (2024) J Mol Struct 1301:137365

    CAS  Google Scholar 

  52. Bal S, Demirci Ö, Şen B, Taslimi P, Aktaş A, Gök Y, Aygün M, Gülçin İ (2021) Arch Pharm 354:e2000422

    Google Scholar 

  53. Demir Y, Duran HE, Durmaz L, Taslimi P, Beydemir Ş, Gulçin İ (2020) Appl Biochem Biotech 190:437

    CAS  Google Scholar 

  54. Demir Y, Taslimi P, Koçyiğit ÜM, Akkuş M, Özaslan MS, Duran HE, Budak Y, Tüzün B, Gürdere MB, Ceylan M, Taysi S, Gülçin İ, Beydemir Ş (2020) Arch Pharm 353:e2000118

    Google Scholar 

  55. Pedrood K, Sherafati M, Mohammadi-Khanaposhtani M, Asgari MS, Hosseini S, Rastegar H, Larijani B, Mahdavi M, Taslimi P, Erden Y, Günay S, Gulçin İ (2021) Int J Biol Macromol 170:1

    CAS  PubMed  Google Scholar 

  56. Türkeş C, Demir Y, Beydemir Ş (2021) J Biomol Struct Dyn 39:1672

    PubMed  Google Scholar 

  57. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA Jr, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Keith T, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09, Revision E.01. Gaussian, Inc, Wallingford, CT

  58. Accelrys Software Inc (2013) Discovery studio modeling environment, Release 3.5. Accelrys Software Inc, San Diego

  59. Momany FA, Rone RJ (1992) Comp Chem 13:888

    CAS  Google Scholar 

  60. Trott O, Olson AJ (2010) J Comput Chem 31:45

    Google Scholar 

  61. Eberhardt J, Santos-Martins D, Tillack AF, Forli S (2021) J Chem Inf Model 61:3891

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Thanks to İnönü University for all of the spectral analysis. The authors thank Esin Akı Yalcin and the research group for technical assistance. The numerical calculations reported in this paper were partially performed at the TUBITAK ULAKBIM High Performance and Grid Computing Center (TRUBA resources).

Author information

Authors and Affiliations

  1. Department of Engineering Basic Sciences, Faculty of Engineering and Natural Sciences, Malatya Turgut Özal University, Malatya, Türkiye

    Ülkü Yılmaz

  2. Department of Pharmacy Services, Nihat Delibalta Göle Vocational High School, Ardahan University, 75000, Ardahan, Türkiye

    Yeliz Demir

  3. Department of Chemistry, Faculty of Arts and Sciences, Gaziantep University, 27310, Gaziantep, Türkiye

    Tuğba Taşkın Tok

  4. Department of Bioinformatics and Computational Biology, Institute of Health Sciences, Gaziantep University, 27310, Gaziantep, Türkiye

    Tuğba Taşkın Tok

  5. Department of Chemistry, Faculty of Science and Arts, İnönü University, 44280, Malatya, Türkiye

    Yetkin Gök

  6. Health Services Vocational School, İnönü University, 44280, Malatya, Türkiye

    Aydın Aktaş

  7. Department of Chemistry, Faculty of Science, Atatürk University, 25240, Erzurum, Türkiye

    İlhami Gülçin

Authors
  1. Ülkü Yılmaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yeliz Demir
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tuğba Taşkın Tok
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yetkin Gök
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aydın Aktaş
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. İlhami Gülçin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ülkü Yılmaz.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 1926 KB)

Supplementary file2 (DOCX 1464 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yılmaz, Ü., Demir, Y., Taşkın Tok, T. et al. Bisbenzimidazole salts and their in silico–in vitro inhibitory abilities on hCA I, hCA II, and AChE enzymes. Monatsh Chem 155, 653–662 (2024). https://doi.org/10.1007/s00706-024-03204-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00706-024-03204-5

Keywords

Search

Navigation