PubMed · 14201418
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H S SUGAR. 1964. GLAUCOMA AND THE PRACTITIONER.. https://pubmed.ncbi.nlm.nih.gov/14201418/
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The interaction of five human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes, that is, hCA I, II, IV, V, and IX with a small library of phosphonic acids/organic phosphates, including methylphosphonic acid, MPA; phenylphosphonic acid, PPA; N-(phosphonoacetyl)-L-aspartic acid, PALA, methylene diphosphonic acid MDPA, the O-phosphates of serine (Ser-OP) and threonine (Thr-OP) as well as the antiviral phosphonate foscarnet has been studied. hCA I was activated by all these compounds, with the best activators being MPA and PPA (K(A)s of 0.10-1.20 microM). MPA and PPA were on the other hand nanomolar inhibitors of hCA II (K(I)s of 98-99 nM). PALA showed an affinity of 7.8 microM, whereas the other compounds were weak, millimolar inhibitors of this isozyme. The best hCA IV inhibitors were PALA (79 nM) and PPA (5.4 microM), whereas the other compounds showed K(I)s in the range of 0.31-5.34 mM. The mitochondrial isozyme was weakly inhibited by all these compounds (K(I)s in the range of 0.09-41.7 mM), similarly to the transmembrane, tumor-associated isozyme (K(I)s in the range of 0.86-2.25 mM). Thus, phosphonates may lead to CA inhibitors with selectivity against two physiologically relevant isozymes, the cytosolic hCA II or the membrane-bound hCA IV.
Direct fluorination of arenemethanesulfonamide anions under mild conditions and in high yield has been accomplished using N-fluorobisbenzenesulfonimide, NFSi, on carbanions of N-tert-butyl- and N-bis-(4-methoxyphenyl-methyl)-benzenemethanesulfonamides giving novel alpha-fluoro- and alpha,alpha-difluoro-benzenemethanesulfonamides respectively: IC(50) and pK(a) data show that alpha-halogenation enhances sulfonamide acidity incrementally and correlates well with increased carbonic anhydrase inhibition, while lipophilicity is also enhanced.
The geometries of 19 biologically active substituted sulfonamides (including clinically useful acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, and brinzolamide) in both neutral and deprotonated forms, were optimized using Becke3LYP/6-311+G(d,p) method (compounds 1-6) and two-layered ONIOM (B3LYP 6-311+G(d,p): MNDO) method (compounds 7-19). The investigated sulfonamides are weak acids with calculated acidity of about 1320-1420 kJ mol(-1). Of acids studied the highest gas-phase acidity (1324 kJ mol(-1)) possesses methazolamide. This drug is, according to the computed pKa value (5.9), also in water solution the most acidic compound of the sulfonamides investigated. The computed pKa values varied between 5.9 and 12.6 and correlate well with the available experimental pKa's found in the literature. Cancerostatic aromatic sulfonamides 16-19 are generally weak acids with the acidity comparable or slightly lower than the lead sulfanilamide. The available experimental partition coefficients of sulfonamides investigated are best reproduced by the IA LOGP method. Computed partition coefficients for antiglaucoma sulfonamides 1-13 varied between -0.47 and 2.61 (IA LOGP). Thus these compounds are only slightly or moderate lipophilic. The lipophilicity of the cancerostatic sulfonamides 14-18 is from relatively narrow interval between -0.07 and 1.68 (IA LOGP). The most potent CAI 10-13 are also the most lipophilic compounds among the antiglaucomatics studied. The available experimental solubilities are best reproduced by the IA LOGS method. The computed solubilities qualitatively correlate with the corresponding lipophilicities, logS increasing as logP declines. The analysis of molecular descriptors defined by Lipinski have been shown that all of the sulfonamides studied obey 'Rule of 5'. Therefore, in the early stages of the design of antiglaucoma sulfonamides, it is becoming more important to determine the pKa, lipophilicity, water solubility, and other physicochemical properties associated with a drug, before synthetic work is undertaken, with the aim of avoiding the synthesis of compounds that are predicted to have poor biopharmaceutical characteristics.