Compound |
hCA IX K | I | (nM) |
hCA XII K | I | (nM) |
20a |
20.2 |
6.0 |
AAZ |
25.0 |
5.7 |
2.4. Benzene Sulfonamido-Coumarinyl Hydrazones Hybrids as CA Inhibitors
Chandak et al., in 2016, synthesized sulfonamide bearing coumarin derivatives by a Hantzsch thiazole synthetic approach as shown in
. In this synthetic strategy, the thiazoyl hydrazine methylidene pyrazole
31
derivatives were achieved from 4-hydrazinobenzenesulfonamide hydrochloride, further converted into pyrazole-based carbaldehyde bearing thiosemicarbazones, and finally reacted to substituted bromoacetyl-based coumarins
30
by condensation reaction. In the second step, different 6-substituted 3-bromoacetylcoumarins
30
and 4-thioureido-benzenesulfonamide achieved 2-amino-substituted-coumarinylthiazoles
32
by condensation reaction. In the next step, heterocyclic series
33
containing three IBTs prepared by treatment of 2-aminobenzothiazole-6-sulfonamide that first obtained from sulfanilamide and 6-substituted-3-bromoacetylcoumarins. On the other hand, the derivatives of series 4, different 3-acetylcoumarins
29
and 4-hydrazinobenzenesulfonamide hydrochloride
34
by refluxing together in aqueous ethanol with anhydrous sodium acetate, give benzenesulfonamido-coumarinyl hydrazones,
35
(
Scheme 4.
Synthesis of sulfonamide bearing coumarin derivatives
31
–
35
.
The following sulfonamide-bearing coumarin scaffold consisted of twenty-four compounds evaluated for the inhibition of hCA I, II, IX and XII (human carbonic anhydrase isoforms). Among all of these, the
32a
compound (
Figure 6) exhibited strong potent inhibitory activity with a K
5) exhibited strong potent inhibitory activity with a K
I
value 2.28 nM (
Table 4
) against hCA IX, as compared to standard compound AZA with a K
I
range 25.0 nM. Moreover, analogues
32a
and
32b
were most potent with K
I
values 0.54 nM against hCA XII when compared to AZA with a K
I
value 5.7 nM. The hybrid structure 4-{2-[1-(2-oxo-2
H
-chromen-3-yl)ethylidene]hydrazino} benzenesulfonamide
35a
revealed the highest activity K
I
= 13.23 nM for hCA II in comparison with reference drug AZA with K
I
value 12.1 nM. The compound 4-{2-[1-(6-bromo-2-oxo-2
H
-chromen-3-yl)ethylidene]hydrazino}benzenesulfonamide
35b
(
Figure 6) screened potent inhibitory activity with a K
5) screened potent inhibitory activity with a K
I
value 21.95 nM against hCA I, as compared to standard compound AZA (acetazolamide) with a K
I
range 250.0 nM (
Table 4
). The SAR showed that the introduction of bromo and unsubstituted H-atom on coumarin increase the carbonic anhydrase inhibitory activity of derivatives
35a
and
35b
(
Figure 6), while the presence of electron-withdrawing Cl-atom and unsubstituted H-atom on coumarin enhances the inhibitory activity of compounds
5), while the presence of electron-withdrawing Cl-atom and unsubstituted H-atom on coumarin enhances the inhibitory activity of compounds
32a
and
Figure 65.
Structures of the most active coumarin sulfonamide CA inhibitors
32a
–
32b
and
35a
–
35b
.
Table 4. Coumarin sulfonamide as CA inhibitors
32a–
32b and
35a–
35b.
Compound Number |
hCA I K | I | (nM) |
hCA II K | I | (nM) |
hCA IX K | I | (nM) |
hCA XII K | I | (nM) |
32a |
263.49 |
21.20 |
2.28 |
0.54 |
32b |
349.63 |
17.46 |
2.54 |
0.54 |
35a |
220.13 |
13.23 |
58.61 |
4.4 |
35b |
21.95 |
1751.72 |
23.59 |
0.62 |
AZA |
250.0 |
12.1 |
25.0 |
5.7 |