Synthesis and carbonic anhydrase I, II, IX and XII inhibitory activity of sulfamates incorporating piperazinyl-ureido moieties

Abstract

A series of sulfamates were synthesized using as lead compound SLC-0111, a sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor in Phase I clinical trials. The new derivatives incorporated ureido moieties as spacers between the benzene sulfamate fragment which binds the zinc ion from the active site, and the tail of the inhibitor, but the urea moieties were part of a substituted piperazine ring system. The derivatives (and some of their phenol precursors) were tested for the inhibition of the cytosolic, hCA I and II (off target isoforms) and the trans-membrane, tumor-associated hCA IX and XII enzymes (anticancer drug targets). Generally hCA I was not effectively inhibited, whereas many low nanomolar inhibitors were evidenced against hCA II (KIs in the range of 1.0–94.4 nM), IX (KIs in the range of 0.91–36.9 nM), and XII (KIs in the range of 1.0–84.5 nM). The best substitution fragments at the piperazine ring included the following moieties: 3-methylphenyl, 2,3-dimethylphenyl, 4-methoxyphenyl, 6-arylpyrimidine-2-yl

Structure-activity relationship with pyrazoline-based aromatic sulfamates as carbonic anhydrase isoforms I, II, IX and XII inhibitors: Synthesis and biological evaluation

“…The purity of the tested compounds was determined by combustion elemental analyses conducted by the Microanalytical Laboratory of the Chemistry Department of the University of Ferrara with a MT-5 CHN recorder elemental analyser (Yanagimoto, Kyoto, Japan) and the values found were within 0.4% of theoretical values. Pyrazolines 7a [51], 7b [52], 7c [53], 7d [44], 7i [52], 7l [54], 15a [55], 15b [55], 15f [55], 16a [43], and sulfamates 8a, 8d, 8e, 8g [44] have been prepared as previously described.…”

“…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].…”

2-Benzylpiperazine: A new scaffold for potent human carbonic anhydrase inhibitors. Synthesis, enzyme inhibition, enantioselectivity, computational and crystallographic studies and in vivo activity for a new class of intraocular pressure lowering agents

“…Other examples of piperazine-based CA inhibitors can be found in the literature [17,18], but to our knowledge, no C-substituted piperazine has been tested so far on hCA.…”

Pyrazole/pyrazoline as an excellent pharmacophore in the design of carbonic anhydrase inhibitors (2018–2022)

“…[72] Excellent-tomoderate hCA inhibitory activity was noticed for evaluated molecules. In case of hCA I, few molecules exerted potent inhibitory activity; among them, compound 45 (Figure 20) In view of the potent anti-CA activity of sulfamates, [73,74] Nocentini et al envisaged synthesis and investigation of the anti-CA activity of pyrazoline-sulfamates. [75] All the evaluated molecules showed moderate hCA I inhibitory activity.…”