Sulfonamides lipophilicity

The amino group is readily dia2oti2ed in aqueous solution, and this reaction forms a basis for the assay of sulfas. Aldehydes also react to form anils, and the yellow product formed with 4-(dimethylamino)hen2a1dehyde can be used for detection in thiu-layer and paper chromatography. Chromatographic retention values have been deterrnined in a number of thiu layer systems, and have been used as an expression of the lipophilic character of sulfonamides (23). These values have corresponded well with Hansch lipophilic parameters determined in an isobutyl alcohol—water system. 

Developing agents must also be soluble in the aqueous alkaline processing solutions. Typically such solutions are maintained at about pH 10 by the presence of a carbonate buffer. Other buffers used include borate and, less frequendy, phosphate. Developer solubiUty can be enhanced by the presence of hydroxyl or sulfonamide groups, usually in the A/-alkyl substituent. The solubilization also serves to reduce developer allergenicity by reducing partitioning into the lipophilic phase of the skin (46). 

Several drug classes, including tetracycline, sulfonamide, and quinolone antibiotics, as well as chlorothiazide, chlorpromazine, and amiodarone hydrochloride, have been shown to be photoantigens. Photosensitivity may persist even after withdrawal of the drug, as has been observed with the antiarrhythmic drug amiodarone hydrochloride, since it is lipophilic and can be stored for extended periods in the body fat (Unkovic et al., 1984). In addition, it is quite common for cross-reactions to occur between structurally related drugs of the same class. 

In addition, the solubilized sulfonamides as a group diffuse very widely into the tissues, penetrating into all fluids, including urine, bile, and milk. The degree of tissue penetration is influenced by several factors, including the ionization state and lipophilicity of the particular sulfonamide, the vascularity of the absorption site, and the degree of protein binding. 

The first entirely synthetic derivative, fluvastatin (see Ref. [19]), and its subsequent derivative, atorvastatin, have a lipid solubility that is intermediate between pravastatin and the lactone prodrugs (see Tab. 4.2), and consequently their liver specificities are less expressed. In order to benefit from selective statin uptake mechanism into the liver cells and thereby decrease passive diffusion into other cell types, the recently introduced rosuvastatin molecule was purposefully made more hydrophilic by the introduction of a sulfonamide group. Indeed, the ratio of IC5 values measured in fibroblasts and hepatocyte cultures became considerable higher than that of atorvastatin (see Tab. 4.1). The pronounced differences of inhibitory potency, lipophilicity and the extent of active OATP-linked transport jointly... 

Figure 10.22 Distribution of three sulfonamides and p-aminobenzoic acid between albumin, plasma water and erythrocytes in humans. Log P values for octonol/woter ore sulfafurazole 1.15 sulfamethoxazole 0.88 and sulfadiazine 0.13. Binding to albumin correlates with lipophilicity.

Bradykinin-related peptides are potent vasoactive molecules implicated in inflammation and pain that mediate their acute actions via two receptors one inductible (Bl) and the other expressed (B2). It appears that a Bl-selective antagoifist would be useful as anti-inflammatory agents. The majority of non-peptidic Bl antagoifists have a basic amine and a lipophilic sulfonamide as exemplified by compound 1 (SR240612, A" = 0.48 nM), the distance between the basic nitrogen and the sulfonamide has been recognized as cracial for binding selectivity to the Bl subtype over the B2. Lead... 

Greater water solubility can also result from a decrease of the crystal lattice energy, the methyl groups hindering the various intermolecular interactions (hydrogen bonds, dipole-dipole bonds, etc.), hi the antibacterial sulfonamide series, the substitution of the pyrimidine ring of sulfadiazine by one, then two, methyl groups causes an increase in solubility (Table 20.3). A priori, one would expect why the methyl substituted derivatives are less soluble. This for the double reason that they show increased lipophilicity and that they are less dissociated than the parent molecule. 

An even more extreme situation is found with carbonic anhydrase inhibitors such as ac-etazolamide, ethoxyzolamide, and methazol-amide, which are useful for the treatment cf glaucoma. Because of their limited aqueous solubility or unfavorable lipophilicity,they are not active when given topically to the eye and must be given orally or parenterally. Systemic side effects severely limit this mode of therapy and, consequently, numerous investigations are presently under way to find a new carbonic anhydrase inhibitor that readily penetrates the cornea or to prepare a prodrug with adequate water solubility and lipophilicity combined with the ability to be reconverted to the parent sulfonamide after corneal passage (255-257). 

The diffusion of small molecules across the sclera has been well characterized. Various sulfonamides diffuse across rabbit sclera (40,41). In patients undergoing cataract surgery, methazolamide, a hydrophilic compound, penetrated the sclera much faster than the cornea, but ethoxzolamide, which is lipophilic, had similar diffusion across the sclera and cornea (40). Other studies also have found greater scleral permeability to hydrophilic molecules than lipophilic ones (42,43). 

Replacement or removal of the sulfonamide group at position 7 yields compounds with little or no diuretic activity. Saturation of the double bond to give a 3,4-dihydro derivative produces a diuretic that is 10-fold more active than the unsaturated derivative. Substitution with a lipophilic group at position 3 gives a marked increase in the diuretic potency. Haloalkyl, aralkyl, or thioether substitution increases the lipid solubility of the molecule and yields compounds with a longer duration of action. Alkyl substitution on the 2-N position also decreases the polarity and increases the duration of diuretic action. Although these compounds do have carbonic anhydrase activity, there is no correlation of this activity with their saluretic activity (excretion of sodium and chloride ions). 

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