New sulfonamides containing organometallic-acylhydrazones: synthesis, characterisation and biological evaluation as inhibitors of human carbonic anhydrases

Abstract

A series of organometallic acylhydrazones was prepared, incorporating Re(CO)3, Mn(CO)3 and ferrocenyl moieties, which were subsequently reacted with amino-sulfonamides in order to obtain carbonic anhydrase (CA, EC 4.2.1.1) inhibitors possessing organometallic moieties in their molecules. The new derivatives were investigated as inhibitors of four human (h) CA isoforms with pharmaceutical applications, such as the cytosolic hCA I, II and VII and the mitochondrial hCA VA. An interesting inhibitory profile against these isoforms was obtained, with some of these metal complexes acting as subnanomolar or low nanomolar inhibitors. They were also thoroughly characterised from the chemical point of view, making them of interest for further developments in the field of metal complexes of sulfonamides with CA inhibitory action.

Novel Re(I) tricarbonyl coordination compounds based on 2-pyridyl-1,2,3-triazole derivatives bearing a 4-amino-substituted benzenesulfonamide arm: synthesis, crystal structure, computational studies and inhibitory activity against carbonic anhydrase I, II, and IX isoforms†

“…(3–116 nM) but higher than those obtained by Alberto et al. (3–7 nM) 14b–d . The introduction of a methylene group between the metallic part and the sulfonamide unit has a slight negative effect on the inhibition values (18.7 nM for 4a vs. 27.3 nM for 4b ), as previously reported 14c .…”

“…(3–7 nM) 14b–d . The introduction of a methylene group between the metallic part and the sulfonamide unit has a slight negative effect on the inhibition values (18.7 nM for 4a vs. 27.3 nM for 4b ), as previously reported 14c . Additionally, a better inhibition is observed with ligands 3a and 3b compared to their corresponding metallic analogs.…”

“…In particular, a very strong inhibition is found for ligand 3a , which displayed 7-fold higher affinity than its rhenium complex 4a ( K i ( 3a )=2.8 nM vs. K i ( 4a )=18.7 nM). This unexpected result should be confirmed on other hCA isoforms, the non-metaled free ligands exhibiting generally weaker affinity than that of the corresponding rhenium complexes 14b . In turn, this first study showed that both rhenium complexes were highly inactive against hCA I and exhibited a low affinity against hCA II but a nanomolar affinity against hCA IX.…”

“…As mentioned in the introduction, the group of Alberto demonstrated that compact tricarbonyl rhenium complexes acted as excellent carbonic anhydrase IX and XII inhibitors, with nanomolar affinities 14c . More recently, Tim Storr et al., reported that tricarbonyl rhenium complexes based on a dipyridylamine (DPA) or an iminodiacetate (IDA) ligands with a pendent benzenesulfonamide pharmacophore exhibited interesting CA-IX inhibition ( K I of 37 nM for the best candidate) 14d .…”

“…While sulfonamides (and bioisosteres sulfamates and sulfamides) are known to possess very efficient carbonic anhydrase inhibitory properties 13 , only a few examples of benzenesulfonamide-based compounds incorporating a [M(CO) 3 ] + complex (M = Re and 99m Tc) have been reported 14 . Among these examples, Alberto and coworkers showed that simple piano-stool-type rhenium complexes with a pendent arylsulfonamide arm inhibited hCA IX and hCA XII with nanomolar affinities 14c . Using a similar strategy, i.e.…”