In silico and in vitro inhibition abilities of novel benzene sulfonamides on carbonic anhydrase and choline esterases

Abstract

Compounds that possess a benzene sulfonamide structure are utilized in a wide range of fields. It is reported in the literature that many compounds belonging to this class of compounds exhibit various pharmacological properties such as antibacterial, antifungal, antiviral, anticancer, inflammatory, antiglaucoma, and anticholinergic effects. Carbonic anhydrase (CA) enzymes play a critical role in pH regulation, long-term synaptic turnover and are therefore thought to be associated with such diseases as mental retardation, Alzheimer’s disease (AD) and Down syndrome. Studies have reported that there is an increase in the levels of hCA-I and hCA-II isoenzymes in AD. AD is a complex, multifactorial disorder, so therapy should probably address not only the cholinergic system but also additional systems. Based on these features, a series of novel substituted benzene sulfonamides were synthesized from 1,2,3-trimethoxy-5-methylbenzene. Sulfonyl chloride 9 was synthesized from the reaction of 1,2,3-trimethoxy-5-methylbenzene and excess chlorosulfonic acid. The reaction of the obtained sulfonyl chloride with NH₃ and N-alkyl amines, aniline, and phenethylamine gave substituted benzene sulfonamide derivatives 10–16. The synthesized compounds were evaluated for their carbonic anhydrase (hCA I-II), acetyl cholinesterase (AChE) and butyryl cholinesterase (BChE) inhibitory properties. Some of the substituted benzene sulfonamide derivatives 10–16 showed inhibitory effect on hCA isoenzymes. The K_i values determined for the hCA I enzyme are in the range of 102.01–147.19 µM. Benzene sulfonamide derivatives 10–16 showed an inhibitory effect on AChE and BChE. The K_i values determined for AChE and BChE enzymes are in the range of 28.76–308.08 µM and 42.80–445.60 µM, respectively. It was determined that sulfonamides 15–16 were selective inhibitors for the hCA I and 10 showed 11-fold more selectivity on AChE than BChE. In addition, the in-silico SAR and ADME properties of the synthesized compounds were also investigated.

Graphical Abstract

Keywords:

• Benzene sulfonamide
• carbonic anhydrase
• anticholinergic properties
• molecular docking
• ADME

Acknowledgments

We are greatly indebted to Ataturk University for financial supports of this work.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

The data that support the findings of this study are available in the supplementary material of this article.