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  • Sulfonamides incorporating ketene N,S-acetal bioisosteres as potent carbonic anhydrase and acetylcholinesterase inhibitors.

Sulfonamides incorporating ketene N,S-acetal bioisosteres as potent carbonic anhydrase and acetylcholinesterase inhibitors.

Archiv der Pharmazie (2020-04-15)
Qëndresa Istrefi, Cüneyt Türkeş, Mustafa Arslan, Yeliz Demir, Arleta R Nixha, Şükrü Beydemir, Ömer I Küfrevioğlu
ABSTRACT

In this study, 15 novel compounds in a series of sulfonamide-based ketenes (7a-o) were synthesized and characterized using Fourier-transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, and mass spectrometry. All compounds were tested for their ability to inhibit the human carbonic anhydrase (hCA) isoforms I and II, and acetylcholinesterase (AChE). The halogen-appended compounds, 7g, 7o, and 7i, exhibited the highest hCA I/II and AChE inhibition, with the KI values in the low nanomolar range (KI  = 9.01 ± 0.08, 7.41 ± 0.03, and 7.37 ± 0.31 nM, respectively), as compared with their corresponding parent 2-[2,2-dicyano-1-(phenylamino)vinylthio]-N-(4-sulfamoylphenyl)acetamide analogs 7a-o. Besides, derivatives 7c and 7e selectively inhibited the isoform hCA I, whereas compounds 7m and 7n selectively inhibited isoform hCA II. These findings indicated that all compounds can inhibit metabolic dysfunctions, such as edema, epilepsy, glaucoma, and Alzheimer's disease, by specifically targeting both the hCA isoforms and AChE expression. Herein, also the interactions between ligands and receptors were highlighted through in silico molecular docking studies. The molecular mechanics-generalized Born surface area method was utilized to compute the binding free energy and the energy contribution of the critical residues in the active site was estimated. All these results would help us to perfectly understand the relationship between activity and structural characteristics of derivatives and to further improve newly and highly effective analogs targeting hCA and AChE.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
5,5′-Dithiobis(2-nitrobenzoic acid), BioReagent, ≥98%, suitable for determination of sulfhydryl groups
Sigma-Aldrich
4-Nitrophenyl acetate, esterase substrate
Sigma-Aldrich
Acetylcholinesterase from Electrophorus electricus (electric eel), Type V-S, lyophilized powder, ≥1,000 units/mg protein