Design, synthesis, spectroscopic characterizations, single crystal X-ray analysis, in vitro xanthine oxidase and acetylcholinesterase inhibitory evaluation as well as in silico evaluation of selenium-based N-heterocyclic carbene compounds

Abstract

Herein, eight new NHC-based selenourea derivatives were synthesized and characterized by using spectroscopic method (¹H, ¹⁹F, and ¹³C NMR, FT-IR), and elemental analysis techniques. These compounds were synthesized by mixing benzimidazolium salts, potassium carbonate, and selenium powder in ethyl alcohol. Additionally, the molecular and crystal structures of the three compounds (1c, 2b, and 2c) were determined using the single-crystal x-ray diffraction (XRD) method. Diffraction analysis demonstrated the partial carbon-selenium double-bond character of these compounds. All compounds were determined to be highly potent inhibitors for AChE and XO enzymes. The IC₅₀ values for the compounds were found in the range of 0.361–0.754 μM for XO and from 0.995 to 1.746 μM for AChE. The DNA binding properties of the compounds were investigated. These compounds did not have a remarkable DNA binding property. Also, DPPH radical scavenging activities of the compounds were also investigated. Compounds (1c), (2a), (3a), and (3b) exhibited more pronounced DPPH radical scavenging activity when compared to other compounds. Docking studies were applied by using AutoDock 4 to determine interaction mechanism of the selected compounds (1a), (1b), and (3b). The compound (1b) has good binding affinity (−9.78 kcal/mol) against AChE, and (−6.86 kcal/mol) for XO target. Drug similarity properties of these compounds compared to positive controls were estimated and evaluated by ADMET analysis. Furthermore, molecular dynamics simulations have been applied to understand the accuracy of docking studies. These findings and the defined compounds could be potential candidates for the discovery and progress of effective medicine(s) for AChE and XO in the future.

Communicated by Ramaswamy H. Sarma

In this study, we synthesized selenourea derivatives from N-heterocyclic carbene (NHC) precursors. All compounds were characterized by using NMR, FTIR spectroscopic method, and elemental analysis technique. In addition, the crystal structure of the three compounds was determined using the single-crystal X-ray diffraction method. New selenoura derivatives were tested for their effect to inhibit the xanthine oxidase and acetylcholinesterase enzymes. The DNA binding properties of the Se-NHC compounds were investigated and the compounds did not have significant DNA binding properties. In addition, DPPH radical scavenging activities of Se-NHC compounds were also investigated. All compounds exhibited DPPH radical scavenging activity. Molecular Docking studies using AutoDock 4 were used to determine the interaction mechanism of selected compounds (1a, 1b, and 3b) Drug similarity properties of these compounds compared to positive controls were estimated and evaluated by ADMET analysis. Furthermore, molecular dynamics simulations have been applied to understand the accuracy of docking studies.

HIGHLIGHTS

1. Selenourea derivatives were synthesized from N-heterocyclic carbene precursors.

2. All compounds were characterized by spectroscopic techniques (NMR and FT-IR) and elemental analyses.

3. All compounds were tested for their effect to inhibit the xanthine oxidase and acetylcholinesterase enzymes.

4. Single-crystal X-ray diffraction method was used to determine the structure of the three compounds

5. DNA binding studies were performed and the compounds did not exhibit DNA binding properties.

6. DPPH testing of compounds was performed and compounds exhibited DPPH radical scavenging activity.

7. Molecular Docking studies using AutoDock 4 were used to determine the interaction mechanism of selected compounds (1a, 1b, and 3b).

8. The potential compound 1b, which showed the best interaction with molecular dynamics studies, was investigated in the 100 ns range with AChE and XO enzyme.

9. It was used to evaluate and validate three potential inhibitory compounds against XO and AChE, including Allopurinol and Donepezil, based on in vitro experiments including molecular docking and ADMET.

Keywords:

• Enzyme inhibition
• molecular dynamic simulation
• N-heterocyclic carbene
• selenourea
• single-crystal

Acknowledgments

The authors thank the İnönü University Faculty of Science Department of Chemistry for the spectroscopy data and characterization of compounds. The authors acknowledge Dokuz Eylül University for the use of the Oxford Rigaku Xcalibur Eos Diffractometer (purchased under University Research Grant No.: 2010.KB.FEN.13).

Disclosure statement

The authors declare that no conflicts of interests.

Funding

The author(s) reported there is no funding associated with the work featured in this article.