3-(ALKYLTHIO)-N-HYDROXYSUCCINIMIDE DERIVATIVES - POTENT INHIBITORS OFHUMAN-LEUKOCYTE ELASTASE

A series of 3-(alkylthio)-N-hydroxysuccinimide derivatives was synthes ized and their inhibitory activity towards human leukocyte elastase (H LE) was investigated. The interaction of the compounds having a 3-alky lthioether side chain (compounds 1 and 2) with HLE was found to involv e rapid acylation of the enzyme, followed by total regain of enzymatic activity within 3 h. Interestingly, compounds 3-8, having an oxidized thioether side chain, were found to be highly effective, time-depende nt, irreversible inhibitors of the enzyme. The k(obs)/I values for com pounds 3-8 ranged between 890 and 24000 M-1 s-1. These findings demons trate that, unlike the physiological inhibitor of HLE (alpha-1-protein ase inhibitor), which is inactivated upon oxidation, low-molecular-wei ght compounds retain and/or show enhanced inhibitory activity towards HLE upon oxidation of the thioether side chain and lay the groundwork for the development of compounds that embody proteinase inhibitory and antioxidant activity.