Discovery of novel 1,3-diaryltriazene sulfonamides as carbonic anhydrase I, II, VII, and IX inhibitors

Suleyman Akocak,Claudiu T Supuran,Nabih Lolak,Silvia Bua

doi:10.1080/14756366.2018.1515933

Suleyman Akocak, Claudiu T Supuran + Show 2 more

Open Access

https://doi.org/10.1080/14756366.2018.1515933

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Abstract

A series of new 1,3-diaryltriazene sulfonamides was synthesised by reaction of diazonium salt of metanilamide (3-aminobenzene sulfonamide) with substituted aromatic amines. The obtained new compounds were assayed as inhibitors of four physiologically and pharmacologically relevant human (h) isoforms of carbonic anhydrases (CA, EC 4.2.1.1), specifically, hCA I, hCA II, and hCA VII (cytosolic isoforms), as well as the tumour-associated membrane-bound isoform hCA IX. All isoforms investigated here were inhibited by the newly synthesised 1,3-diaryltriazene sulfonamide derivatives from the micromolar to the nanomolar range. The cytosolic isoforms were inhibited with Kis in the range of 92.3–8371.1 nM (hCA I), 4.3–9194.0 nM (hCA II), and 15.6–9477.8 nM (hCA VII), respectively. For the membrane-bound tumour-associated isoform hCA IX, the KI-s ranged between 50.8 and 9268.5 nM. The structure–activity relationship (SAR) with these newly synthesised metanilamide derivatives are discussed in detail.

Highlights

Carbonic anhydrases (CAs, known as carbonate dehydratase, EC 4.2.1.1) are metalloenzymes present in Archaea, prokaryotes and eukaryotes, that catalyse the efficient interconversion of CO2 to HCO3À and protons via a ping-pong mechanism under physiological conditions[1,2,3,4,5,6]
The rationale behind the design of these new 1,3-diaryltriazene sulfonamide derivatives presented in this work is based on our recent report[11], in which we showed that novel 1,3-diraryltriazenesubstituted sulfonamide derivatives possess interesting CA inhibitory properties
We decided to apply the same procedure by changing of position of the sulfonamide moiety from para to meta, in order to investigate whether the potency comes from triazene linker or the position of the sulfonamide zinc-binding group

Summary

Introduction

Carbonic anhydrases (CAs, known as carbonate dehydratase, EC 4.2.1.1) are metalloenzymes present in Archaea, prokaryotes and eukaryotes, that catalyse the efficient interconversion of CO2 to HCO3À and protons via a ping-pong mechanism under physiological conditions[1,2,3,4,5,6]. 15 different isoforms have been described, all belonging to the a-CA family, with some of them being cytosolic (hCA I-III, VII, and XIII), others membrane-bound (hCA IV, IX, XII, and XIV), two mitochondrial (hCA VA and VB), as well as one of them secreted in saliva and milk (hCA VI) Since these isoforms play an important role in acid–base regulation, gluconeogenesis and other biosynthetic reactions, electrolyte secretion, bone resorption/calcification, and tumorigenicity, their inhibition/activation may be exploited in several diseases, including, glaucoma, obesity, neuropathic pain, arthritis, Alzheimers’ disease, and more recently cancer[1,2,3,4,5,6]. In continuation of our recent interest in CAIs11, in this work, we report the synthesis and hCA I, II, VII, and IX inhibitory activity of new 1,3-diaryltriazene sulfonamides 4(a–h) obtained from the reaction of the diazonium salt of metanilamide with different substituted aromatic amines (Figure 3)

Materials and methods

Results and discussion

Conclusions

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