Ординатура / Офтальмология / Английские материалы / Carbonic Anhydrase Its Inhibitors and Activators_Supuran, Scozzafava, Conway_2004

TABLE 5.8

Heterocyclic Sulfonamides Studied by Casha

a Cash, G.G. (1995) Structural Chemistry 6, 157–160.

For the pooled group of benzenesulfonamides and heteroaromatic sulfonamide inhibitors of bovine CA B (CA I) given in Table 5.8 and Table 5.9, Cash (1995) found correlations with molecular connectivity indices. Disregarding five of their heteroaromatics they obtained the following equation:

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TABLE 5.9

Benzenesulfonamides Used in Connectivity

Index QSAR by Casha

a Cash, G.G. (1995) Structural Chemistry 6, 157–160.

(n = 45, r = 0.91, s = 0.39, F = 101)

Saxena and Khadikar (1999) found correlations of subsets of previously studied compounds (Supuran and Clare 1998; Equations 5.7 and 5.8; Table 5.5) with the Wiener index. Whereas five subsets gave good correlations for CA II and three subsets gave good correlations for CA I, the correlations for the complete sets were r = 0.2338 and 0.2512, respectively. This does not seem significant enough.

Mattioni and Jurs (2002) published a study of the large series of CAIs, including both benzenoid and heteroaromatic inhibitors of CA I, CA II and CA IV of Scheme 5.2, using a mixture of topological, electronic and geometric, and hybrid descriptors. They used mainly neural nets as their QSAR method, and although they obtained extremely good data fits (Figure 5.1), their use of neural nets and difficult- to-interpret descriptors precludes any physical interpretation of their results. These methods do, however, enable one to predict activities.

5.2.6 DIRECT BINDING STUDIES

In addition to approaches that consider the ligand only, there are those that deal with the interaction of the ligand with the enzyme on the molecular mechanics level. Menziani et al. (1989b) transformed p-chlorobenzenesulfonamide into benzenesulfonamide in the presence of the enzyme in a molecular dynamics simulation, obtaining a G∞ for the difference within 2.5 kJ mole–1 of the experimental value.

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FIGURE 5.1 Fit of a large group of sulfonamide CA I inhibitors by using neural nets. TSET: training set, CVSET: cross-validation set and PSET: prediction set. (From Mattioni, B.E., and Jurs, P.C. (2002) Journal of Chemical Information and Computer Science 42, 94–102. With permission.)

Menziani et al. (1989a) calculated energies for free molecules and CA-bound complexes for 20 benzenesulfonamides separated into a number of components: BE =

ECA–S + ESD + ECAD, where ECA–S is the total interaction energy of enzyme with ligand and ECAD and ESD are distortion energies for the enzyme and ligand, respectively.

The calculated binding energies were related to calculated AM1 MO descriptors, such as charges on the atoms of the sulfonamide moiety and the HOMO energy of the ligand.

5.3 HETEROAROMATICS

Many highly potent heterocyclic sulfonamide inhibitors of CA have been synthesized, and some are in clinical use as diuretics and intraocular pressure (IOP) lowering drugs and other types of drugs.

5.3.1 CHARGE AND DIPOLE MOMENT

The first significant study of the QSAR of heteroaromatics (Kishida 1978) used the Huckel theory to calculate for the series of nine amine N-substituted 5-amino-1,3,4- thiadiazole-2-sulfonamides given in Table 5.10 charges, atom–atom polarizabilities, HOMO and LUMO energies and electrophilic and nucleophilic superdelocalizabilities of the various atoms. These parameters and also the hydrophobicity π calculated by summing substituent contributions were correlated with CA inhibitory properties. It was found that in this series the electronic properties of the sulfonamide moiety varied little and there was no correlation with HOMO energy, but there was a strong correlation with LUMO energy (R = 0.9439). He obtained the following equation:

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TABLE 5.10

Aminothiadiazole Sulfonamides

Studied by Kishidaa

a Kishida, K. (1978) Chemical and Pharmaceutical Bulletin 26, 1049–1053.

where QN is the charge on the 5-nitrogen atom, suggesting that the atoms in the 5-position interact hydrophobically and electrostatically with the enzyme. Nine compounds, however, are rather few for a QSAR.

DeBenedetti’s group (DeBenedetti et al. 1987; Menziani and DeBenedetti 1991a) used the same approach as that for the benzenoids. They (Menziani et al. 1989a) calculated with AM1 quantum chemical indices for the twelve 2-substituted 1,3,4-thiadiazole-5-sulfonamides given in Table 5.11. They calculated by molecular mechanics binding energies to bovine CA B and correlated CA inhibitory potency with binding energy as well as binding energy with quantum indices:

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TABLE 5.11

Heteroaromatic Sulfonamides Studied by DeBenedetti et al.a

a De Benedetti, P.G. et al. QSAR 6, 51–53.

where BE is the binding energy, EH the energy of the HOMO and QSA the sum of the charges on the atoms of the SO2NH– moiety.

Clare and Supuran (1997) in a quantum chemical study of the heterogeneous group of sulfonamides shown in Table 5.12, which included benzenoid, bicyclic and heteroaromatic compounds, used a set of descriptors that did not require that the

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TABLE 5.12

Mixed Group of Sulfonamides Studied by Clare and Supurana

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TABLE 5.12 (continued)

Mixed Group of Sulfonamides Studied by Clare and Supurana

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TABLE 5.12 (continued)

Mixed Group of Sulfonamides Studied by Clare and Supurana

N

a Clare, B.W., and Supuran, C.T. (1997) European Journal of Medicinal Chemistry 32, 311–319. With permission from Elsevier.

series be congeneric, beyond including a sulfonamide moiety. They also used a statistical technique, ACE, which models nonlinearity. They obtained the following equation:

− log KI = 61.0(±11.5)QN + 1.82(±0.43)EL + 0.592(±0.091)Ax

+ 0.484(±0.166)Ay′ − 0.434(±0.093)D − 0.919(±0.242) log P′ (5.24) + 8.41(±3.01)

(n = 20, R2 = 0.864, s = 0.678)

where QN is the charge on the sulfonamide N; EL the LUMO energy; Ax and Ay the longest and second longest orthogonal dimensions of the molecule, respectively, determined from the moments of inertia; D the magnitude of the dipole moment; and log P the lipophilicity determined by using the program ClogP. The piecewise linear term Ay′ is equal to Ay if Ay > 6.0 and equal to 6.0 otherwise; similarly, log P′ is equal to log P if log P > 0.35 and equal to 0.35 otherwise. This kind of nonlinear dependence on log P is well known, and can imply a kinetic effect of partitioning between compartments. The statistical significance of nonlinearity in Ay is not particularly good, but if it is valid implies that activity increases with increasing breadth, provided it is at least 6 Å wide.

Supuran and Clare (1999) carried out a quantum chemical QSAR study of the group of 40 (mainly aryl) 5-aminosulfonyl-substituted 1,3,4-thiadiazole- and thia-

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TABLE 5.13

Aliphatic Sulfonamides Studied by Maren and Conroya

a Maren, T.H., and Conroy, C.W. (1993) A new class of carbonic anhydrase inhibitor.

Journal of Biological Chemistry 268, 26233–26239.

diazoline-2-sulfonamide inhibitors of CA I and CA II given in Table 5.13. For CA I, the results for the pooled data were not as good as those of the two groups separately and were affected by two highly influential cases. For the thiadiazoles, the best equation was:

− log IC50 = −59.43(±6.57)QS − 0.1359(±0.0325)μ x + 0.0300(±0.0116)μz

(5.25)

+ 0.0204(±0.0073) HS − 98.87(±10.30)QO − 27.83(±10.39)

(n = 20, R2 = 0.909, s = 0.18)

where QS and QO are the charges on the primary sulfonamide S and O atoms, respectively; μx and μz the components of the dipole moment along the ring C-sul- fonamide S bond and that normal to the thiadiazole ring, respectively; and HS is the calculated solvation energy. For the thiadiazolines, the best equation for CA I inhibition was:

− log IC50 = −0.00847(±0.0014)Πyy + 5.871(±1.791)QS + 1.787(±0.367)EH

+ 82.3(±17.76)QO1 + 16.36(±4.16)QO2 + 182.6(±32.8) (n = 20, R2 = 0.917, s = 0.21)

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where Πyy is the intermediate diagonal component of the polarizability tensor referred to the inertial axes; QS the charge on the secondary sulfonamide S; EH and EL the HOMO and LUMO energies, respectively; HS the solvation energy; and QO1 and QO2 the charges on the oxygen atoms of the primary and secondary sulfonamide groups, respectively.

For CA II inhibition by thiadiazoles the best equation was:

− log IC50 = −63.34(±6.97)QS + 0.696(±0.204)EH − 0.1346(±0.0345)μ x

− 104.7(±10.6)QO − 22.46(±11.49)

(n = 20, R2 = 0.902, s = 0.18)

where QS and QO are the charges on the primary sulfonamide S and O, respectively, and EH, HS, μx and μz are as defined previously.

No satisfactory equation could be obtained for CA II inhibition by thiadiazolines. For CA IV inhibition by thiadiazoles the best equation obtained was:

− log IC50 = −0.00736(±0.00104)Πxx + 18.90(±6.72)QN

(5.28)

− 0.1228(±0.0452)μ x + 22.29(±7.78)

(n = 20, R2 = 0.760, s = 0.29)

where Πxx is the largest component of the polarizability tensor, QN the charge on the primary sulfonamide N and μx the component of the dipole moment as defined previously.

For CA IV inhibition by the thiadiazolines, the equation obtained was:

− log IC50 = −0.00729(±0.00122)Πyy + 1.628(±0.384)EH

(5.29)

− 0.0977(±0.0226)μ x + 105.4(±21.5)QO + 208.9(±40.1)

(n = 20, R2 = 0.822, s = 0.25)

where QO is the charge on the primary sulfonamide oxygen and the other symbols are as defined previously. It should be noted that Equations 5.25 to 5.29 are good fits, but because a fairly large number of parameters was fitted to only 20 compounds they are not good predictors.

Equation 5.20 and Equations 5.23 to 5.29 contain at least one term involving the charge on one or more atoms on a primary sulfonamide group. Several also involve the dipole moment or its component along the C–S bond linking this group to the heterocyclic ring. This supports the long-held belief that electrostatic effects

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