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of human carbonic anhydrase II by solution-phase and solid-
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compounds (I-1, I-2, I-3) exhibit improved solubility
(Table 1) and can be easily prepared in the form of
All three new compounds were each assayed for
hCA I, hCA II, hCA IV and hCA XII isozymes binding
by stopped flow technique and results of which are
presented in Table 1. According to in vitro assays these
compounds can be characterized as isozyme-specific
inhibitors. ey were a relatively weak inhibitors of hCA
XII with IC50 of about 520–740 nmol/L, derivative I-2
containing benzene-1,4-disulfonamide moiety being
most active. e activity of benzene-1,4-disulfonamide
derivatives I-2 and I-3 towards isoenzyme hCA I is very
high and comparable with their analogous activity for
hCA II (Table 1). However, while the pharmacological
function of hCA I is still not clear, for effective lowering
of intraocular pressure, 99.99% inhibition of CA II and
98% inhibition of CA IV is required26. e activity of
compounds I-1, I-2 and I-3 towards hCA II and hCA IV
is different, but this difference is not regular. I-1 being
2.8 times, I-2 7.5 times and I-3 6.2 times more active for
hCA II. e small preference of aromatic sulfonamides
towards CA II in comparison with CA IV was observed
for the largest majority of these derivatives2. Compounds
I-2 and I-3 containing two sulfonamide moieties interact
with pharmacologically important hCA II and hCA IV
much stronger (Table 1).
14. Remko M, von der Lieth CW. eoretical study of gas-phase
acidity, pKa, lipophilicity, and solubility of some biologically active
sulfonamides. Bioorg Med Chem 2004;12:5395–5403.
15. Remko M. Molecular structure, pKa, lipophilicity, solubility
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sulfonamides. eochem J Mol Struct 2010;944:34–42.
Conclusions
ree novel potent inhibitors of hCA I, hCA II, hCA IV
and hCA XII has been discovered using operator directed
drug design techniques and synthesis of limited num-
ber of new aromatic sulfonamides. is strategy led to
synthesis of new derivatives with improved solubility
while maintaining CA activity. Derivatives containing
benzene-1,4-disulfonamide group being more active
than structure with the 4-sulfamoylbenzamide moiety.
e inhibitors studied have been shown a net preference
for hCA II in comparison with hCA IV.
16. Remko M, Kožíšek J, Semanová J, Gregáň F. Synthesis, crystal and
molecularstructureoftwobiologicallyactivearomaticsulfonamides
and their hydrochloride salts. J Mol Struct 2010;973:18–26.
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inhibition of the enzyme carbonic anhydrase. 1. Substituted
benzenedisulfonamides. J Med Chem 1978;21:845–850.
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anhydrase. I. Stop-flow kinetic studies on the native human
isoenzymes B and C. J Biol Chem 1971;246:2561–2573.
19. Pacchiano F, Carta F, Vullo D, Scozzafava A, Supuran CT.
Inhibition of β-carbonic anhydrases with ureido-substituted
benzenesulfonamides. Bioorg Med Chem Lett 2011;21:102–105.
20. Kolayli S, Karahalil F, Sahin H, Dincer B, Supuran CT.
Characterizationandinhibitionstudiesofanα-carbonicanhydrase
from the endangered sturgeon species Acipenser gueldenstaedti.
J Enzyme Inhib Med Chem 2011;26:895–900.
Declaration of interest
e authors report no conflicts of interest.
21. Innocenti A, Scozzafava A, Supuran CT. Carbonic anhydrase
inhibitors. Inhibition of cytosolic isoforms I, II, III, VII and XIII
with less investigated inorganic anions. Bioorg Med Chem Lett
2009;19:1855–1857.
22. Scozzafava A, Briganti F, Ilies MA, Supuran CT. Carbonic
anhydrase inhibitors: Synthesis of membrane-impermeant low
molecular weight sulfonamides possessing in vivo selectivity for
the membrane-bound versus cytosolic isozymes. J Med Chem
2000;43:292–300.
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