Synthesis and pharmacological effects of novel benzenesulfonamides carrying benzamide moiety as carbonic anhydrase and acetylcholinesterase inhibitors.

Mehtap Tuğrak,Halise İnci Gül,İlhami Gülçi̇n,Barış Anil

doi:10.3906/kim-2007-37

Abstract

N -(1-(4-Methoxyphenyl)-3-oxo-3-((4-( N -(substituted)sulfamoyl)phenyl)amino)prop-1-en-1-yl)benzamides 3a – g were designed since sulfonamide and benzamide pharmacophores draw great attention in novel drug design due to their wide range of bioactivities including acetylcholinesterase (AChE) and human carbonic anhydrase I and II (hCA I and hCA II) inhibitory potencies. Structure elucidation of the compounds was carried out by 1H NMR, 13C NMR, and HRMS spectra. In vitro enzyme assays showed that the compounds had significant inhibitory potential against hCA I, hCA II, and AChE enzymes at nanomolar levels. Ki values were in the range of 4.07 ± 0.38 – 29.70 ± 3.18 nM for hCA I and 10.68 ± 0.98 – 37.16 ± 7.55 nM for hCA II while Ki values for AChE were in the range of 8.91 ± 1.65 – 34.02 ± 5.90 nM. The most potent inhibitors 3g (Ki = 4.07 ± 0.38 nM, hCA I), 3c (Ki = 10.68 ± 0.98 nM, hCA II ) , and 3f (Ki = 8.91 ± 1.65 nM, AChE) can be considered as lead compounds of this study with their promising bioactivity results. Secondary sulfonamides showed promising enzyme inhibitory effects on AChE while primary sulfonamide derivative was generally effective on hCA I and hCA II isoenzymes.

Highlights

Owing to significant bioactivities of benzamide pharmacophores, this group of compounds has been used for designing novel and effective bioactive compounds
NH protons belong to benzamide moieties indicating open-ring forms of the compounds (3a–g, Figure 2) were in the range of 10.54–10.09 ppm and 10.12–10.09 ppm as singlet. -NH2 protons belonging to primary sulfonamide moiety were seen at 7.28 ppm while other -NH protons of the secondary sulfonamides were seen in the range of 12.71–10.39 ppm as singlet
Our results indicated that 3a–g had effective inhibition profiles against slow cytosolic isoform hCA I, and cytosolic dominant rapid isoenzyme hCA II with inhibition constants in the low nanomolar range 4.07 ± 0.38 – 29.70 ± 3.18 nM, and 10.68 ± 0.98 – 37.16 ± 7.55 nM, respectively by considering Ki values

Summary

Introduction

Owing to significant bioactivities of benzamide pharmacophores, this group of compounds has been used for designing novel and effective bioactive compounds. Benzamide and its derivatives have been reported with antimicrobial, analgesic anticancer, carbonic anhydrase inhibitory, cholinesterase inhibitory activities and so on [1,2,3,4]. One of the diseases that affects elderly people is Alzheimer’s disease (AD) which is a neurodegenerative disease that causes progressive dementia [5,6]. It is a global economic and social burden. While AChE levels in the brain reduce, the activity of BuChE either does not change, or in some cases increases. AChE inhibitors are the most used medication in the treatment of AD which act as irreversible or reversible inhibitors. Even though some valuable progress has been made in the treatment of AD, we still urgently need to find out more selective and effective antiAD drugs with less side effects than the ones available on the market [11]

Methods

Results

Conclusion