Synthesis and human carbonic anhydrase I, II, VA, and XII inhibition with novel amino acid–sulphonamide conjugates

Hasan Küçükbay,Nesrin Buğday,F Zehra Küçükbay,Andrea Ageli,Gianluca Bartolucci,Claudiu T Supuran

doi:10.1080/14756366.2019.1710503

Hasan Küçükbay, Nesrin Buğday + Show 4 more

Open Access

https://doi.org/10.1080/14756366.2019.1710503

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Abstract

A series of amino acid–sulphonamide conjugates was prepared through benzotriazole mediated coupling reactions and characterised by 1H-NMR, 13C-NMR, MS, and FTIR spectroscopic techniques as well as elemental analysis. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was determined against four human (h) isoforms, hCA I, hCA II, hCA VA, and hCA XII. Most of the synthesised compounds showed effective in vitro CA inhibitory properties. The new amino acid–sulphonamide conjugates showed potent inhibitory activity against hCA II, some of them at subnanomolar levels, exhibiting more effective inhibitory activity compared to the standard drug acetazolamide. Some of these sulphonamides were also found to be effective inhibitors of hCA I, hCA VA, and hCA XII, with activity from the low to high nanomolar range.

Highlights

The environmentally friendly synthesis of biologically active molecules is one of the most important issues in medicinal chemistry1
Synthesis of new sulphonamide derivatives is an active research topic for organic and pharmaceutical chemists8,9. Both sulphonamides10–12 and amino acids13–15 have been reported to have various biological activities, but there are few reports of their successful combination in one molecule as a hybrid drug candidate16–18. Due to their antimicrobial and CA inhibitory properties, both primary and secondary sulphonamide derivatives are under investigation to determine compounds possessing the highest activity with possibly few side-effects19,20
The syntheses of novel homosulphonamide and 4-aminoethylsulphonamide–amino acid conjugates prepared in this study are shown in Scheme 1

Summary

Introduction

The environmentally friendly synthesis of biologically active molecules is one of the most important issues in medicinal chemistry. The widespread use of sulphonamide antibacterials leads to the development of bacterial resistance For this reason, the development of novel classes of antimicrobial compounds with less side effect and improved selectivity is urgently needed. Synthesis of new sulphonamide derivatives is an active research topic for organic and pharmaceutical chemists8,9 Both sulphonamides and amino acids have been reported to have various biological activities, but there are few reports of their successful combination in one molecule as a hybrid drug candidate. Both sulphonamides and amino acids have been reported to have various biological activities, but there are few reports of their successful combination in one molecule as a hybrid drug candidate16–18 Due to their antimicrobial and CA inhibitory properties, both primary and secondary sulphonamide derivatives are under investigation to determine compounds possessing the highest activity with possibly few side-effects. Following our synthetic and CA inhibition screening work on dipeptide and N-protected amino acid–sulphonamide conjugates, we synthesised and explored the inhibitory activity of new N-protected amino acid–sulphonamide conjugates against hCA I, II, VA, and XII enzymes, in the search of more effective and isoform-selective CA inhibitors (CAIs)

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