Parallel synthesis and in vitro activity of novel anthranilic hydroxamate-based inhibitors of the prostaglandin H2 synthase peroxidase activity.

Currently available non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin are directed at the cyclooxygenase (COX) site, but not the peroxidase (POX) activity of prostaglandin H2 synthase (PGHS). They are thus unable to inhibit the free-radical induced tissue injury associated with PGHS peroxidase activity, which can occur independently of the COX site. A lead compound, anthranilic hydroxamic acid (AHA) was found to have significant PGHS-POX inhibitory activity (IC50= 72 microM). To define the critical parameters for PGHS-POX inhibition, we investigated 29 AHA derivatives, synthesised from their acid precursors, using solid phase synthesis. In vitro analysis demonstrated a ten-fold improvement in inhibition with 3,5-diiodoanthranilic hydroxamic acid (IC50= 7 microM).

A convenient parallel synthesis of low molecular weight hydroxamic acids using polymer-supported 1-hydroxybenzotriazole.

A convenient two-step procedure for the parallel synthesis of hydroxamic acids from carboxylic acids and hydroxylamine in good to high yields is reported. It involves the formation of a polymer-bound HOBt active ester and subsequent reaction with O-protected or free hydroxylamine. The hydroxamates are isolated with high purities by simple evaporation of volatile solvents. The use of free hydroxylamine leads to increased yields while maintaining high purities. Recycling of the spent resin to produce the same or a different hydroxamic acid has been achieved by a three-step protocol which is easily amenable to automation and cost-economical. The method presented here is well suited to the preparation of the title compounds and can be used effectively to synthesise large molecules containing a hydroxamic acid group.