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Novel bis-ureido-substituted sulfaguanidines and sulfisoxazoles as carbonic anhydrase and acetylcholinesterase inhibitors

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Abstract

To discover alternative substances to compounds used to treat many diseases, especially treating Alzheimer’s disease (AD) and Parkinson’s disease targeting carbonic anhydrase (hCA) and acetylcholinesterase (AChE) enzymes, is important. For this purpose, a series of novel bis-ureido-substituted sulfaguanidine (SG1–4) and sulfisoxazole (SO1–4) derivatives were synthesized, and their inhibitory capacities were screened against hCA isoenzymes (hCA I and II) and AChE. Possible binding mechanisms of inhibitors to the active site were elucidated by in silico studies, and the results were supported by in vitro results. Moreover, the percent radical scavenging capacities of the derivatives were also evaluated. The derivatives (SG1–4 and SO1–4) were more effective against hCAs compared to standard drug acetazolamide (KI values of 98.28–439.17 nM for hCA I and II, respectively) and exhibited the highest inhibition with the KIs in the ranges of 2.54 ± 0.50–41.02 ± 7.52 nM for hCA I, 11.20 ± 2.97–67.14 ± 13.58 nM for hCA II, and 257.60 ± 27.84–442.60 ± 52.13 nM for AChE. Also, compounds SG1 and SO1 also showed ABTS radical scavenging activity at the rate of 70% and 78%, respectively. These results will contribute to the literature for the rational design and synthesis of new potent and selective inhibitors targeting hCAs and AChE with multifunctional effects such as radical scavenging as well as inhibition.

Graphical abstract

This study focused on the synthesis and inhibitory effects of bis-ureido-substituted sulfaguanidine (SG1–4) and sulfisoxazole (SO1–4) derivatives against human hCA I and II isoforms and AChE. In order to test synthesized derivatives’ free radical scavenging potentials were the DPPH and ABTS assays. In silico studies elucidated possible binding mechanisms of inhibitors to the active site.

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Acknowledgements

This work was supported by the Research Fund of Anadolu University (Grant Number 2102S003).

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Adıyaman University, 02040, Adiyaman, Turkey

    Nebih Lolak & Süleyman Akocak

  2. Department of Chemistry, Faculty of Arts and Sciences, Harran University, 63290, Şanlıurfa, Turkey

    Mustafa Durgun

  3. Department of Medical Biochemistry, Faculty of Medicine, Kafkas University, 36100, Kars, Turkey

    Hatice Esra Duran

  4. Department of Pharmacy Services, Vocational School of Health Services, Harran University, 63300, Şanlıurfa, Turkey

    Adem Necip

  5. Department of Biochemistry, Faculty of Pharmacy, Erzincan Binali Yıldırım University, 24002, Erzincan, Turkey

    Cüneyt Türkeş

  6. Department of Bioengineering, Faculty of Engineering, Bilecik Şeyh Edebali University, 11230, Bilecik, Turkey

    Mesut Işık

  7. Department of Biochemistry, Faculty of Pharmacy, Anadolu University, 26470, Eskişehir, Turkey

    Şükrü Beydemir

  8. The Rectorate of Bilecik Şeyh Edebali University, 11230, Bilecik, Turkey

    Şükrü Beydemir

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  1. Nebih Lolak
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Lolak, N., Akocak, S., Durgun, M. et al. Novel bis-ureido-substituted sulfaguanidines and sulfisoxazoles as carbonic anhydrase and acetylcholinesterase inhibitors. Mol Divers 27, 1735–1749 (2023). https://doi.org/10.1007/s11030-022-10527-0

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