Research paperStructure-activity relationship with pyrazoline-based aromatic sulfamates as carbonic anhydrase isoforms I, II, IX and XII inhibitors: Synthesis and biological evaluation
Graphical abstract
Introduction
Pyrazoline ring is a privileged structure in medicinal chemistry because of its wide spectrum of pharmacological activities. A number of pyrazoline derivatives have been reported for their antibacterial [1], antimalarial [2,3], anti-inflammatory [4], MAO inhibitory [5,6], antioxidant [7,8], neuroprotective [9], antidepressant [10] and anticancer activity [[11], [12], [13], [14], [15], [16], [17], [18]]. Furthermore, several series of pyrazoline derivatives displayed carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity [[19], [20], [21], [22], [23], [24], [25]]. CAs are a superfamily of metalloenzymes that catalyze the CO2 hydration/dehydration reaction, and are classified into seven genetically distinct families, named α-, β-, γ-, δ-, ζ-, η-, and ɵ-CAs [[26], [27], [28]]. All human (h) CAs are α-class enzymes [28]. Fifteen different human isoforms have been identified and characterized to date, among which twelve are catalytically active (hCAs I-IV, VA, VB, VI, VII, IX, XII-XIV). Human CAs can be further categorized into four different subsets depending on their subcellular localization. Among those identified, hCA I, II, III, VII, VIII, X, XI, XIII are cytosolic proteins, hCA VA and VB are present in the mitochondrial matrix, hCA VI is a secreted enzyme, hCA IV is a glycosylphosphatidylinositol (GPI)-anchored protein and hCA IX, XII and XIV are trans-membrane isoforms [26,28]. These enzymes are widely distributed in many tissues and organs where they are implicated in a wealth of pivotal physiological processes. Dysregulated expression and/or abnormal activity of hCAs can result into severe pathological conditions [26,[29], [30], [31], [32]]. hCA IX and XII have been validated as markers of disease progression in many hypoxic tumors and their targeted inhibition has been associated with a significant reduction of the growth of both primary tumors and metastases [26]. In contrast, ubiquitous isoforms hCA I and II are the main off-target isoforms because their promiscuous inhibition might lead to undesired side effects [26]. CA inhibitors (CAIs) can be clustered into several different groups considering their binding mode to the enzyme active site, among which the zinc-binders are the most effective and thus most investigated for drug-design purposes [33]. Within this subset, sulfonamides are the ideal zinc-binding group (ZBG) owing to a peculiar combination of interactions that this moiety can solely establish with the zinc ion and the residues nearby [33]. Pyrazoline sulfonamides were recently reported as CA inhibitors [34] and as dual CA and AchE inhibitors [[35], [36], [37], [38], [39]]. Bioisosteric replacement of the sulfonamide with the sulfamate group, one of sulfonamide most related congeners, produced interesting examples of CAs selective inhibitors [[40], [41], [42], [43]]. These considerations led us to report a small library of pyrazoline sulfamates displaying interesting profile and selectivity as CA inhibitors [44]. Here, we have extended these studies to have full SAR of this class of compounds.
Section snippets
Chemistry
The synthetic pathway to obtain N1-acetyl-3,5-diaryl-4,5-dihydropyrazole bearing a sulfamate group at 4- or 3-position on 3-aryl ring (compounds 8a-m and 9a-m, Scheme 1) and on 5-aryl ring (compounds 17a-h and 18 a-h, Scheme 2) started with the preparation of chalcones (4, 5, 14 and 15) through the Claisen-Schmidt condensation [[45], [46], [47]] between substituted acetophenone (1, 2 and 10) and substituted benzaldehydes (3, 11 and 12) in methanol in the presence 50% aqueous NaOH. Chalcones
Conclusions
Four new series of aromatic sulfamates were synthesized by a sulfamoylation reaction of the corresponding phenolic precursors. The reported derivatives bearing 3,5-diarylpyrazoline moieties as spacers between the benzenesulfamate fragment which binds the zinc ion from the active site, and the tail of the inhibitor were investigated for the inhibition of four human hCAs, namely the cytosolic hCA I and II (off target isoforms) and the trans-membrane, tumor-associated hCA IX and XII enzymes
General methods
All commercially available solvents and reagents were used without further purification. NMR spectra were recorded on an Inova 500 spectrometer (Varian, Palo Alto, CA, USA). The chemical shifts (δ) are reported in part per million downfield from tetramethylsilane (TMS), which was used as internal standard. The spectra were recorded in hexadeuteriodimethylsulphoxide (DMSO‑d6). Infrared spectra were recorded on a Vector 22 spectrometer (Bruker, Bremen, Germany) in Nujol mulls. The main bands are
Acknowledgements
This study was supported in part by FIR grants from the University of Cagliari, Italy (to V.O. and G.B.).
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These authors equally contribute to the present paper.