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174

Carbonic Anhydrase

in the neighborhood of the sulfonamide group, and, in particular, the readiness of that group to deprotonate are of major importance in the QSAR of these substances.

5.3.2 STERIC VARIABLES AND POLARIZABILITY

Equation 5.24 for the compounds given in Table 5.12 involves the longest and second-longest linear dimensions of the molecule, and is the only equation in which steric effects were apparent. Both are in the direction of activity increasing with the size of the molecule, and Ax is of high statistical significance. Polarizability occurs in Equations 5.26 and 5.29 (the intermediate component) and Equation 5.28 (the largest component). In all three cases, a more polarizable molecule is less active.

5.3.3 LIPOPHILICITY

Only Equations 5.20 and 5.24 involve lipophilicity: in the first case high lipophilicity leads to high activity, whereas in the second it leads to low activity if log P exceeds 0.35.

5.3.4 QUANTUM MEASURES OTHER THAN CHARGE

Equations 5.23, 5.24, 5.26, 5.27 and 5.29 contain EH, EL or both. In each case, the activity of the drug increases with increasing energy. Solvation energy occurs in Equations 5.25 to 5.27. For Equation 5.25, the more solvated drugs are more active, whereas for Equation 5.26 and 5.27 they are less active.

5.3.5 TOPOLOGICAL INDICES

Gao and Bajorath (1999) computed binary and conventional QSARs for many sulfonamides, amides, alcohols and other compounds, the structures of which they did not give. They obtained good correlations, both conventional (R2 = 0.84) and cross-validated (Q2 = 0.82), with the atomic valence connectivity indices 1χν and 0 χν, the Kier shape indices 1κ and 2κ, and the sum of atom–atom polarizabilities apol, an indicator variable for the presence of unsubstituted sulfonamide, and linear and quadratic terms in log P. The work by Mattioni and Jurs (2002) on a mixed series of CAIs has been mentioned previously (Section 5.2.5)

5.3.6 DIRECT BINDING

DeBenedetti’s group (Menziani and DeBenedetti 1991b) used the AMBER molecular mechanics force field to calculate binding energies of both benzene and thiadiazole sulfonamides to HCA C, and related the calculated binding energies to total charge on SO2NH– N and CA inhibitory activity:

log II50 = 106.82(±12.66)qO – 1.24(±0.15)I + 57.90(±6.58)

(5.30)

(n = 48, r = 0.945, F = 183.5)

 

Copyright © 2004 CRC Press, LLC

QSAR Studies of Sulfonamide Carbonic Anhydrase Inhibitors

175

where I is an indicator variable for benzene. For the thiadiazoles:

 

log II50 = –0.199(±0.034)BE – 4.84(±1.29)

(5.31)

(n = 12, r = 0.96, F = 105.5)

 

5.4 ALIPHATICS

Until recently, the generally accepted idea was that aliphatic sulfonamides are very poor CA inhibitors (Maren 1984, 1987, 1991). Maren and Conroy (1993) showed that strong CA inhibitors can be designed and obtained from this class of sulfonamides too.

Figure 5.2 shows the linear correlation between pKa and KI for the nine aliphatic sulfonamides given in Table 5.14. Thus, the simplest derivative, CH3SO2NH2, with a pKa ca. 11 is an extremely weak CA inhibitor, whereas with polyhalogenoalkylsulfonamides increasing pKas show an increasing potency of inhibitory power. CF3SO2NH2, the most acidic sulfonamide ever reported, with a pKa of 5.9, is one of the most potent CA inhibitors obtained, with a KI of 2 nM (for CA II at 0∞C; Maren and Conroy 1993). Some of these compounds are also topically active sulfonamides for lowering elevated IOP in glaucoma.

5.4.1 CHARGE AND DIPOLE MOMENT

In a series of aryl, alkyl and aralkyl-sulfonylmethanesulfonamides and -thiomethane- sulfonamide inhibitors of human CA II (Scholz et al. 1993), the sulfonyl compounds were found to be much more active, probably because of the enhancement of acidity

i pK

−3

−4

−5

−6

−7

−8

−9

6

7

8

9

10

11

12

pKa

FIGURE 5.2 Plot of log inhibitory constant vs. pKa for a group of aliphatic CA II inhibitors described by Maren, T.H., and Conroy, C.W. (1993) Journal of Biological Chemistry 268, 26233–26239.

Copyright © 2004 CRC Press, LLC

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

SO

CI

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

F

 

 

F

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CF3SO2CI

 

 

n-C4FJgSJO2CI

 

 

 

 

 

 

 

 

 

 

 

 

n-C8F17SO2CI

 

 

 

 

 

 

C8F17COCI

 

A

 

 

 

 

 

 

 

B

 

 

 

 

 

 

F

 

 

F

 

 

 

 

 

 

D

 

 

 

 

 

 

 

 

E

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

F

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

C

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

SO

2

NH

2

 

 

SO

NH

2

 

SO

 

NH

2

 

 

SO

NH

2

 

 

 

 

SO

NH

 

 

SO

NH

 

 

 

 

 

 

 

 

2

 

 

 

 

2

 

 

 

 

2

 

 

 

 

 

 

 

 

2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2

 

 

2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

NH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

NH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2

 

NH

 

 

 

 

 

 

NHNH

 

 

 

CH

 

NH

 

 

 

CH

CH

 

NH

 

 

 

 

 

 

 

 

 

 

2

 

 

 

2

 

 

 

 

 

2

 

 

 

2

 

 

2

2

 

 

1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2

 

 

 

 

2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

3

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

4

 

 

 

 

 

5

 

 

 

 

 

 

 

6

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

SO

NH

2

SO

NH

2

 

 

SO

 

NH

 

 

 

 

 

 

SO

2

NH

2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2

 

 

 

2

 

 

 

 

2

2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

H

N

 

 

 

 

 

 

 

CI

 

 

 

 

 

 

 

 

 

 

 

N

N

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

H

N

 

S

 

 

SO

NH

2

 

 

 

Br

 

 

 

I

 

 

CI

 

 

 

SO

NH

 

 

 

 

 

 

SO

NH

2

2

 

 

 

 

 

2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2

 

 

 

 

 

 

2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

13

 

 

 

NH

2

 

 

 

NH

2

 

 

 

 

 

CI

 

 

 

 

 

 

 

 

 

 

NH

2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

9

 

 

 

10

 

 

 

 

 

11

 

 

 

 

 

 

 

 

12

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

COCI

 

 

 

 

 

F

 

 

 

F

 

 

 

 

F

 

 

 

F

 

 

 

 

 

 

F

 

 

 

 

 

 

 

 

F

 

 

 

SO

2

NH

2

 

SO

2

NH

2

 

 

 

 

 

 

 

F

 

 

 

CI

NH

2

 

 

 

NH

2

 

 

 

 

 

 

 

 

 

7

 

 

 

 

8

 

 

 

 

H

C

 

 

 

 

 

 

 

3

 

 

 

 

 

 

 

 

 

N

 

N

 

 

 

 

HN

 

S

SO

2

NH

2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

14

 

 

 

Copyright © 2004 CRC Press, LLC

176

Anhydrase Carbonic

 

 

 

 

 

N

N

 

 

 

 

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

H

 

NCH

CH

CONH

S

SO

NH

2

 

 

 

H

N

 

S

N

2

2

2

 

2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2

 

 

 

H

 

 

 

 

 

15

 

 

 

 

 

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

16

 

 

 

 

O

 

 

 

 

 

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

H

N

 

S

N

 

SO

NH

2

 

 

 

 

 

 

2

 

 

 

 

H

 

 

2

 

H

N

 

S

N

 

 

 

 

 

O

 

 

 

 

 

2

 

 

 

H

 

 

 

 

 

 

 

 

 

 

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

18

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

19

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

H

C

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

3

 

 

 

 

N

N

 

 

 

 

 

 

 

 

 

 

O

 

N

N

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

SO

NH

 

 

 

H2N

 

 

 

 

S

N

S

SO

NH

2

 

S

2

 

 

 

 

 

 

2

 

 

 

2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

O

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

17

 

 

 

 

SO

NH

 

 

H

 

SO

NH

 

 

 

 

 

 

 

 

 

2

 

N

 

 

 

 

 

 

 

 

 

 

 

2

 

 

 

2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2

 

 

 

 

 

N

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

N

 

 

 

 

H

N

 

S

SO

NH

2

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2

 

 

 

 

 

N

 

 

 

 

 

 

 

2

 

 

 

 

 

 

 

 

 

 

 

NH

2

 

 

 

 

 

 

21

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

20

 

 

 

 

 

 

 

 

 

 

 

 

 

 

SO

NH

2

SO

 

NH

2

 

 

 

 

 

 

 

 

 

 

 

2

 

 

2

 

 

 

 

 

 

 

 

 

N

 

 

 

 

N

 

 

 

 

 

 

 

S

SO2NH2

HOCH

CH

O

S

SO

NH

2

 

 

 

 

HO

2

 

 

 

 

 

 

 

2

2

 

 

 

 

 

 

 

 

 

 

22

 

 

 

 

23

 

 

CH

OH

CH

CH

OH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

2

 

2

2

 

 

 

 

 

 

 

 

 

 

24

 

25

 

SCHEME 5.2

 

 

 

 

 

 

 

 

 

 

 

 

 

Copyright © 2004 CRC Press, LLC

Inhibitors Anhydrase Carbonic Sulfonamide of Studies QSAR

177

178

Carbonic Anhydrase

of the sulfonamide by the electronegative sulfonyl group. Increasing the size or hydrophobicity of the aryl, alkyl and aralkyl group also increased activity. Thus the equations:

–log IC50 = –3.29 + 1.43(±0.53)ΣσI

(5.32)

(n = 13, r2 = 0.40, s = 0.77, F = 7.34)

–log IC50 = –3.78 + 2.85(±0.66)ΣσI + 0.95(±0.34) size

(5.33)

(n = 13, r2 = 0.66, s = 0.60, F = 9.8)

− log IC50 = −4.84 + 0.32(±0.06)C log PR + 2.91(±0.35)ΣσI

− 1.28(±0.19)

(5.34)

size

(n = 13, r2 = 0.91, s = 0.32, F = 31.89)

where ΣσI is the sum of the Taft inductive parameters of substituents on the α carbon,

size the increased size of the α substituents over hydrogen and ClogPR the hydrophobicity of the R substituent. Equations 5.33 and 5.34 differ in the sign of the

correlation with size.

5.5 CONCLUSIONS

The two studies of DeBenedetti and coworkers (DeBenedetti et al. 1987; Menziani and DeBenedetti 1991a) described previously are the most suggestive and agree that in separate simple congeneric series, substituted benzenes and substituted aminothiadiazoles, good positive correlations are found with total charge on the sulfonamide in each case. This is also consistent with the studies of Kakeya et al. (1960a, 1969b, 1969c, 1970) that relate activity to pKa of the SO2NH2 group, and influences thereon, such as Hammett σ value of substituents.

It is always easier to obtain a good relationship when the number of compounds is small and their variability is limited. Some of the more recent studies have pooled the different drug types and introduced more variation, and are correspondingly more difficult to interpret. They do, however, allow the examination of less significant influences on activity and also show some differences between the QSARs of the different isozymes. In some cases, even the sign of correlation with a descriptor varies from series to series. This can happen when for a particular descriptor there is an optimal value, and the range of values differs between the groups of drugs. Other anomalies might reflect genuine differences between isozymes. Thus, Equations 5.9 and 5.10 reflect a difference in dependence on polarizability between CA I and CA II by the benzenedisulfonamides, which is counter to that for the inhibition of CA I by thiadiazolines in Equation 5.26.

Equations 5.1–5.11, 5.13, 5.14, 5.17, 5.20 and 5.23–5.34 have terms involving either the charge on one or more atoms of the SO2NH2 group or a Hammett σ or

Copyright © 2004 CRC Press, LLC

QSAR Studies of Sulfonamide Carbonic Anhydrase Inhibitors

179

Taft inductive term. The charge on the sulfonamide H in these series is weakly positively correlated with that on S, and the two are strongly negatively correlated with those on N and O. The separation of charge in this group of atoms is a significant but not dominant contribution to the local dipole index Dl. More positive charge on the sulfonamide S and more negative charge on the N or O lead to more activity in most cases. Other quantities modify activity: in general, a larger size and polarizability and a greater solvation energy lead to lesser activity.

Equations 5.12, 5.18, 5.19 and 5.21 exclude charge and inductive terms by design, leaving only Equations 5.15, 5.16 and 5.22, which involve EH or EL. These energies are also involved in the more complex relationships of Equations 5.9, 5.11, 5.26, 5.27 and 5.29. Dependence of activity on EH and EL is negative for CA II (with the exception of Equation 5.27) and CA IV and positive for CA I. This suggests a way of achieving selectivity. Lipophilicity, an important consideration in many QSAR studies, enters into Equations 5.2–5.5, 5.10–5.14, 5.20, 5.24 and 5.34. The sign is positive in all cases but Equation 5.12, in which there is a complex dependence on three π values, and in Equation 5.24 (HCA II).

Consideration of the orientation of the nodes in the π-like orbitals on benzenoid compounds, as in Equation 5.17, leads to more readily interpretable QSAR, and this is particularly so if the symmetry of benzene is properly taken into account (Supuran and Clare, in press). This problem was avoided by the studies by Kakeya’s and DeBenedetti’s groups by their choice of compounds.

ACKNOWLEDGEMENTS

We are indebted to Elsevier for providing permission to reproduce Table 12 from Clare, B.W., and Supuran, C.T. (1007) European Journal of Medicinal Chemistry

32, 311–319; Table 5 from Supuran, C.T., and Clare, B.W. (1998) European Journal of Medicinal Chemistry 33, 489–500; and Table 6 from Supuran, C.T., and Clare, B.W. European Journal of Medicinal Chemistry 34, 463–474. We also thank the publishing house of the Romanian Academy for providing permission to publish Tables 7 and 10 from the review Maren, T.H., Clare, B.W., and Supuran, C.T. (1994) Structure–activity studies of sulfonamide carbonic anhydrase inhibitors. Romanian Chemical Quarterly Reviews 2, 259–282.

REFERENCES

Altomare, C., Tsai, R.-S., el Tayar, N., Testa, B., Carotti, A., Cellamare, S., and DeBenedetti, P.G. (1991a) Determination of lipophilicity and hydrogen bond donor acidity of bioactive sulfonyl-containing compounds by reversed phase HPLC and centrifugal partition chromatography and their application to structure–activity relationships.

Journal of Pharmacy and Pharmacology 43, 191–197.

Altomare, C., Tsai, R.-S., El Tayar, N., Testa, B., Carrupt, P.-A., Carotti, A., and DeBenedetti, P.G. (1991b) Assessment of hydrogen bond donor acidity of bioactive sulfonylcontaining compounds by CCCC. In QSAR: Rational Approaches to the Design of Bioactive Compounds, Silipo, C., and Vittoria, A. (Eds.), Elsevier, Amsterdam, pp. 139–142.

Copyright © 2004 CRC Press, LLC

180

Carbonic Anhydrase

Amat, L., and Carbo-Dorca, R. (1999) Simple linear QSAR models based on quantum similarity measures. Journal of Medicinal Chemistry 42, 5169–5180.

Blacklock, T.J., Sohar, P., Butcher, J.W., Lamanec, T., and Grabowski, E.J.J. (1993) An enantioselective synthesis of the topically active carbonic anhydrase inhibitor MK-0507: 5,6-dihydro-(S)-4-(ethylamino)-(S)-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide hydrochloride. Journal of Organic Chemistry 58, 1672–1679.

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6 Metal Complexes

of Heterocyclic

Sulfonamides as

Carbonic Anhydrase

Inhibitors

Joaquín Borrás, Gloria Alzuet, Sacramento Ferrer

and Claudiu T. Supuran

CONTENTS

 

6.1

Introduction ..................................................................................................

183

6.2

Acetazolamide Complexes...........................................................................

184

6.3

Methazolamide Complexes..........................................................................

192

6.4

Benzolamide Complexes..............................................................................

195

6.5

Complexes Containing Other Sulfonamide CAIs .......................................

200

6.6

Applications of Metal Complexes of Sulfonamides in Therapy.................

202

References..............................................................................................................

203

This chapter reviews the synthesis, characterization and inhibitory properties of complexes of heterocyclic sulfonamide carbonic anhydrase inhibitors (CAIs). The different chelating properties of acetazolamide, methazolamide and benzolamide are described on the basis of crystal structures of Cu(II), Zn(II), Ni(II) and Co(II) complexes. These complexes show interesting applications in the mechanistic studies of carbonic anhydrases (CAs) as well as in the development of clinically useful derivatives, because this enzyme is involved in critical physiological/physiopathological processes.

6.1 INTRODUCTION

The importance of sulfonamides as pharmacological agents was realized when Dogmack (1935) showed that sulfanilamide was the metabolite of the antibacterial drug Prontosil. Later, many sulfanilamide derivatives were synthesized, character-

0-415-30673-6/04/$0.00+$1.50

183

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