Bioorganometallic derivatives of 4-hydrazino-benzenesulphonamide as carbonic anhydrase inhibitors: synthesis, characterisation and biological evaluation

Jeremie Brichet,Rodrigo Arancibia,Emanuela Berrino,Claudiu T Supuran

doi:10.1080/14756366.2020.1724995

Abstract

A series of bio-organometallic-hydrazones of the general formula [{(η5-C5H4)-C(R)=N–N(H)-C6H4-4-SO2NH2}]MLn(MLn = Re(CO)3, Mn(CO)3, FeCp; R=H, CH3) were prepared by reaction of formyl/acetyl organometallic precursors with 4-hydrazino-benzenesulphonamide. All compounds were characterized by conventional spectroscopic techniques (infra-red, 1H and 13C NMR, mass spectrometry and elemental analysis). Biological evaluation as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors agents was carried out using four human/h) isoforms, hCA I, II, IX and XII. The cytosolic isoforms hCA I and II were effectively inhibited by almost all derivatives with inhibition constants of 1.7–22.4 nM. Similar effects were observed for the tumour-associated transmembrane isoform hCA XII (KIs of 1.9–24.4 nM). hCA IX was less sensitive to inhibition with these compounds. The presence of bio-organometallic or metallo-carbonyl moieties in the molecules of these CAIs makes them amenable for interesting pharmacologic applications, for example for compounds with CO donating properties.

Highlights

The carbonic anhydrases (CAs, EC 4.2.1.1) constitute a superfamily of enzymes in all living organism, their essential role being that of catalysing the reversible hydration of CO2 to bicarbonate and protons[1,2,3,4,5]
All compounds were characterised by electron impact (EI) mass spectrometry, elemental analysis, infra-red and NMR spectroscopies (Supporting Information)
A strong molecular ion was shown in the mass spectrum of each organometallic-hydrazone, in addition to the detection of notable successive losses of CO ligands for the cyrhetrenyl (1a–b) and cymantrenyl (2a–b) derivatives (Supplementary Figure S1†)

Summary

Introduction

The carbonic anhydrases (CAs, EC 4.2.1.1) constitute a superfamily of enzymes in all living organism, their essential role being that of catalysing the reversible hydration of CO2 to bicarbonate and protons[1,2,3,4,5]. In a-CAs, this step is generally assisted by a His residue situated in the middle part of the active site, named proton shuttling residue[2,3,4,5,6,7], whereas for other CA genetic families the nature and positioning of the proton shuttle residue is less well understood[8,9,10,11,12,13] Inhibition of these enzymes with various classes of CA inhibitors (CAIs) has an extended range of pharmacologic applications, starting with diuretics and antiglaucoma agents[14], to antiepileptics[15], antiobesity[16], or antitumor drugs[17] and ending with antineuropathic pain[18] anti-ischemia[19] and anti-arthritis drugs[20].

Materials

CA inhibition studies

Results and discussion

Conclusion

Disclosure statement