Acetylsalicylic acid Salicin
(2-[Hydroxymethyl]phenyl-|3-D-glycoside) Figure 1.7 Chemical structures of selected salicylates.
aspirin or the structurally different, more potent anti-inflammatory compounds, NSAID (Section 4.2.2) and acetaminophen (paracetamol). Nevertheless, salicylate is still being used as an external medication, for example, in ointments because of its antiseptic and keratolytic properties.
Despite its disappearance from internal medicine, the pharmaceutical and biological properties of salicylate are of considerable pharmacological interest because this compound is the primary metabolite of aspirin and responsible for many of its biological actions including salicylate poisoning (Section 3.1.1). Salicylate shows a peculiar physico-chemical behavior because of the formation of a ring structure by hydrogen bridging. This requires a hydroxy group in a close neighborhood of the carboxyl group and is only seen with the o-hydro-xybenzoic acid salicylic acid (Figure 1.8) but not with its m- and p-analogues. The o-position of the hydroxyl group facilitates the release of a proton with decreasing pH by increasing the mesomery of the resulting anion. These properties are biologically relevant for the protonophoric actions of salicylates in the uncoupling of oxidative phosphory-lation by eliminating the impermeability of cell membranes to protons (Section 2.2.3). In addition, they help understand the local irritation of the stomach mucosa subsequent to direct contact with the compound and its incorporation into mucosal cells (Section 3.2.1). The m- and p-hydroxy analogues of benzoic acid do not share these properties with salicylate and are biologically largely inactive.
Structure-activity studies of 80 salicylate-type compounds for uncoupling oxidative phosphorylation in isolated mitochondria showed that the essential phar-macophore for this activity is a compound with a negatively charged (carboxyl) group at the o-position, that is, acetylsalicylate. The m- and p-hydroxybenzoate analogues of salicylic acid failed to do so. This suggested
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