1,3,4-Thiadiazole derivatives as selective inhibitors of iNOS versus nNOS: Synthesis and structure-activity dependence

Abstract

The synthesis of new compounds with a 1,3,4-thiadiazole structure, and their in vitro biological evaluation as inhibitors of both neuronal and inducible Nitric Oxide Synthase (nNOS and iNOS) is described. These compounds have been designed by an isosteric modification of a series of 4,5-dihydro-1H-pyrazole derivatives, previously described as the nNOS inhibitors. The insertion of the S atom in the heterocyclic ring induces a selective inhibition of the iNOS isoform. Some of these compounds show as iNOS inhibition percentage near of 100% at a concentration of 50 μM, and the IC50 values measured for the more potent compounds are in a range of 20–40 μM.