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†

Abstract

In this work, two bidentate 2-pyridyl-1,2,3-triazole ligands (3a and 3b) containing a 4-substituted benzenesulfonamide pharmacophore prepared by classical click chemistry procedures, as well as their corresponding rhenium complexes, 4a and 4b of general formula [ReCl(CO) 3 (L)] (L ¼ 3a or 3b) were prepared and fully characterised by spectroscopic methods (IR, NMR, MS, UV-Vis), elemental analysis, X-ray diffraction, and theoretical studies using DFT and TD-DFT methods. In particular, we showed that, in the solid state, the pyridine and the triazole rings of 3b adopted an uncommon cis configuration which stems from intermolecular hydrogen bonds. Preliminary assays demonstrated a promising nanomolar inhibitory activity against carbonic anhydrase isoform IX for both ligands and complexes with a strong affinity K i of 2.8 nM for ligand 3a. More interestingly, complex 4b exhibited a pronounced selectivity against hCA IX over the off-targets hCA I and hCA II which makes this compound a promising potential anticancer drug candidate.

Synthesis, Crystal Structure, Inhibitory Activity and Molecular Docking of Coumarins/Sulfonamides Containing Triazolyl Pyridine Moiety as Potent Selective Carbonic Anhydrase IX and XII Inhibitors

“…Given the remarkable activities of the diverse types of sulfonamide/coumarin CA inhibitors, and as a continuation of our previous studies in the field of potent carbonic anhydrase inhibitors based on tricarbonyl rhenium(I) complexes [24], we hypothesized that the substitution of the sulfonamide pharmacophore grafted to our rhenium complex with a coumarin derivative could improve both the activity and the selectivity of our drugs against hCA IX and also hCA XII isoforms. In the present study, we describe a convenient synthesis of two tricarbonyl rhenium(I) complexes, based on bidentate pyridine-triazole ligands functionalized either by the bioactive 4-substituted benzenesulfonamide or a coumarin moiety, and using an ethylene bridge as a spacer in order to minimize sterical interference between the metallic chelating centre and the pharmacophore.…”

“…The mild reaction conditions associated with the click approach allowed the preparation of a large number of mono-functionalized pyta derivatives in which 1,4-disubstituted 1,2,3-triazoles form an integral part of the metal chelating system (so called "click-to-chelate" concept) [64,65]. We were the first group to use this "click-tochelate" concept to develop tricarbonyl rhenium(I) complexes as carbonic anhydrase IX inhibitors [24]. It should be noted that while numerous 1,2,3-triazole-based CA inhibitors have been reported, the triazole ring (formed by the CuAAC reaction) only acts as a connector between the pharmacophore (coumarin/sulfonamide derivatives) and a metal complex or an organic moiety [66][67][68][69][70][71][72][73].…”

“…Most of the synthesized compounds (organic ligands and metallic complexes) showed promising activity in the nanomolar range for hCA IX isozymes. More interestingly, one of these coordination compounds showed pronounced selectivity against hCA IX over the off-target isoforms, hCA I and hCA II [24]. These encouraging results motivated us to pursue our interest in exploring this interesting class of tricarbonyl rhenium(I) complexes as potential anti-cancer drugs.…”

“…These rhenium(I) complexes showed a significant in vitro inhibitory effect, with high selectivity against tumour-associated hCA IX targets, implying that interactions between the [Re(CO) 3 ] + core and the amino acid residues of the CA active site cavity entrance could enhance the inhibitory potency. In this regard, in a recent paper, we investigated the inhibitory effects of two benzenesulfonamide-based 1,2,3-triazole-pyridine derivatives (so-called pyta) and their corresponding fac-Re(CO) 3 coordination compounds on human cytosolic hCA isoforms I and II, and the membraneassociated hCA IX isoform [24]. Most of the synthesized compounds (organic ligands and metallic complexes) showed promising activity in the nanomolar range for hCA IX isozymes.…”

Photophysical and Electrocatalytic Properties of Rhenium(I) Triazole-Based Complexes

“…In this regard, the copper(I) catalysed 1,3-dipolar cycloaddition of alkynes and azides to form 1,4-disubstituted-1,2,3-triazoles has become a popular transformation in the design of ligands for transition metal complexes over the past decade [5][6][7][8]. This has resulted in several reports on the preparation of 1,2,3-triazole-based rhenium(I) complexes [9][10][11][12][13][14][15][16][17][18][19][20], which have been applied for their therapeutical activity [21][22][23][24][25] and as luminescent biological imaging microscopy probes [26][27][28][29][30][31][32][33][34]. Recently, Ching et al reported a series of complexes of the form [Re(NˆN)(CO) 3 Cl], where the NˆN ligand is based on a 4-(pyrid-2-yl)-1,2,3-triazole framework [35].…”