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

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.

A series of 3-acyl-5-(2-amino-5-substituted-phenyl)-2,2-dimethyl-2,3-dihydro-1,3,4-thiadiazole derivatives were designed, synthesized and evaluated as inhibitors of both neuronal and inducible Nitric Oxide Synthase (nNOS and iNOS).Figure optionsDownload as PowerPoint slideHighlights
► Final compounds have been synthesized using Lawesson’s Reagent, followed by acylation in N-3 and reduction of nitro group.
► Compounds behave as good iNOS inhibitors, being those which take a methoxy group in the aromatic ring the best ones.
► Seven of the compounds (most of them with an electron-donating substituent in R1) exhibit good selectivity iNOS versus nNOS.
► IC50 value of the most potent compounds show an inhibition range between 21.88 and 41.02 μM, being 9h the most potent.