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

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Supuran, C.T., and Scozzafava, A. (2002b) Matrix metalloproteinases (MMPs). In Proteinase and Peptidase Inhibition: Recent Potential Targets for Drug Development, Smith, H.J., and Simons, C., Eds., Taylor & Francis, New York, pp. 35–61.

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Wistrand 1987), motion and altitude sickness (Evans et al. 1976; Forster 1982) and many other conditions (Maren 1984, 1987, 1991; Maren et al. 1993; Lindskog and Wistrand 1987).

Many aromatic, heterocyclic, and, more recently, aliphatic sulfonamides (Maren and Conroy 1993) have been synthesized and tested for their CA inhibitory properties (Maren, 1984, 1987, 1991; Maren et al. 1993; Supuran 1993) and some of them are widely used clinical or investigational drugs, such as acetazolamide 5.1, methazolamide 5.2, ethoxzolamide 5.3 or the thienothiopyran derivative 5.4, MK-972 which together with some closely related congeners are candidates for being clinically used as topical inhibitors to manage glaucoma. (Maren 1984, 1987, 1991; Maren et al. 1993; Blacklock 1993).

SCHEME 5.1

Early structure–activity correlations in this class of drugs were quite simple, leading Maren (1976) to state that perhaps “the criteria for activity in this class are the simplest in pharmacology.” Indeed, all unsubstituted sulfonamides of the type RSO2NH2, where R is generally an aromatic/heterocyclic moiety (Supuran 1993), but can also be a polyhalogenoalkyl one (Evans et al. 1976; Forster 1982; Wright et al. 1983), show inhibitory properties toward this enzyme. When the number and variety of compounds examined increase, modifying influences come to light and the quantitative structure–activity relationships (QSARs) become more complex.

Sulfonamides bind in the ionized form (RSO2NH–) to the zinc ion within the CA active site, as the fourth ligand, substituting the zinc-bound water molecule and perturbing in this way the entire catalytic cycle (Silverman and Lindskog 1998; Silverman 1983, 1990; Liljas et al. 1994).

Considering the clinical importance of these agents per se and because they constitute the starting point for obtaining other classes of widely used pharmacological agents, such as thiazide diuretics, high-ceiling diuretics (of the furosemide type) and certain antithyroid compounds (Silverman 1983, 1990), reviews on struc- ture–activity correlations are available (Maren 1967, 1984, 1987, 1991; Maren et al. 1993, 1994; Supuran 1993; Lindskog and Wistrand 1987) and several important QSAR studies have also been published. This chapter reviews the QSAR work in

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the field of CA inhibitors, such as the different classes of compounds included, the types of correlations performed, the mathematical models obtained and their impact on designing novel inhibitors and the understanding of their mechanism of action at the molecular level. Some original work from our laboratories is also referenced.

5.2 BENZENOID AROMATICS

Derivatives of benzenesulfonamide are among the first known CA inhibitors and were the first for which QSAR results were obtained.

5.2.1 ELECTRONIC CORRELATES

The earliest QSAR studies on benzenesulfonamide derivatives indicated that the electric charge induced on the atoms of the sulfonamide moiety itself was the dominant determinant of CA inhibitory activity. Thus, empirical parameters such as the pKa and 1H NMR chemical shift (Kakeya et al. 1969a, 1969b, 1969c, 1970) of the sulfonamide protons, the Hammett σ constant of substituents on the benzene ring (Kakeya et al. 1969a, 1969b, 1969c, 1970; Hansch et al. 1985; Carotti et al. 1989) the force constant of the S–O bond, (Kakeya et al. 1969a, 1969b, 1969c, 1970) and calculated variables such as components of the dipole moment (Supuran and Clare 1998; Clare and Supuran 1999) and Mulliken and electrostatic potential-based charges (Supuran and Clare 1998; Clare and Supuran 1999; DeBenedetti and Menziani 1985; DeBenedetti et al. 1985) on the atoms of the sulfonamide group correlate with CA inhibitory activity. Another electronic parameter notionally related to lipophilicity and polarity is solvation energy, calculated as the difference in the heat of formation calculated as usual in an isolated molecule and that calculated in a medium with a high dielectric constant, using a continuum model for the solvent. Lipophilicity includes entropic contributions not present in the calculated solvation energy.

Kaketa et al. (1969a, 1969b, 1969c, 1970) gave the following equations for the set of 16 m- and p-substituted benzenesulfonamide inhibitors of CA (commercial, probably a mixture of CA I and CA II; Table 5.1):

where R is the multiple correlation coefficient, s the standard error of estimate, n the number of compounds, σ the empirical Hammett constant and π the Hansch constant for the substituent.

Hansch et al. (1985) carried out similar calculations for the set of 29 monosubstituted benzenesulfonamide inhibitors of human CA II (Table 5.2) and obtained the following equation:

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TABLE 5.1

Benzenesulfonamides in the Study by Kakeya et al.a

a Kakeya, N. et al. (1969a) Chemical and Pharmaceutical Bulletin 17, 1010–1018; Kakeya, N. et al. (1969b) Chemical and Pharmaceutical Bulletin 17, 2000–2007; Kakeya, N. et al. (1969c) Chemical and Pharmaceutical Bulletin 17, 2558–2564; Kakeya, N. et al. (1970) Chemical and Pharmaceutical Bulletin 18, 191–194.

where P is the octanol–water distribution coefficient, and the indicator variables I1 is 1 for m-substitution and 0 otherwise and I2 is 1 for o-substitution and 0 otherwise. This implies that m-substituted compounds are 100 times and o-substituted compounds 2000 times weaker inhibitors than the corresponding p-substituted benzenesulfonamides.

Carotti et al. (1989) studied the series of m- and p-monosubstituted benzenesulfonamide inhibitors of bovine CA B (now designated CA I; Table 5.3) and obtained the following equations:

log 1/Ki = 1.04(±0.37)σ + 0.52(±0.12)π – 0.65(±0.25)I1 + 5.98(±0.16) (5.4)

(n = 31, r = 0.898, s = 0.320, F4,27 = 37.3)

and

log 1/Ki = 0.95(±0.33)σ + 0.54(±0.12)π – 0.35(±0.11)B5,3 + 6.29(±0.22) (5.5)

(n = 31, R = 0.914, s = 0.294, F4,27 = 45.6)

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TABLE 5.2

Sulfonamides used in QSAR calculations by Hansch et al.a

a Hansch, C. et al. (1985) Molecular Pharmacology 27, 493–498.

where I1 is an indicator variable for m-substitution and B5,3 the Sterimol parameter for the substituent, which is a steric measure. The lipophilicity π was measured by the shake flask method.

DeBenedetti et al. (1985) reported a CNDO/2 study of the 25 monoand disubstituted benzenesulfonamide inhibitors of bovine CA B (CA I; Table 5.4), calculating the Mulliken charges on the atoms of the sulfonamide moiety and HOMO and LUMO energies. They found relationships among the lipophilicity, the force constant of the S–O bond, the Hammett σ constant and the pKa and the chemical shift of the sulfonamide protons with qSA, the total calculated charge on the SO2NH2 moiety. They gave the following equation:

(n = 23, r = 0.896, s = 0.292, F = 85.33)

Supuran and Clare (1998) in an AM1 quantum theoretical study of a series of Schiff’s bases (Table 5.5) of sulfanilamide with substituted benzaldehyde and heteroaromatic aldehydes related CA inhibitory activity to a large number of theoretically calculated indices. They found that activities correlated marginally better for values calculated in solution by the COSMO technique and charges based on electrostatic potential distribution than those from a vacuum calculation and Mulliken population analysis.

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