Novel tetrahydroindazolyl-hydrazones and tetrahydroindazolyl-hydrazono-thiazolidin-4-ones - Synthesis, characterization and biological evaluation

In this work, dimedone carbothioamides 3 were condensed with hydrazine hydrate in equimolar ratio to produce tetrahydro-4H-indazol-4-one derivatives 4. Reaction of carbothioamides 3 with excess hydrazine hydrate yielded novel tetrahydro-1H-indazole-3-amine derivatives 5. Thiosemicarbazone derivatives 6 of tetrahydroindazoles, when treated with chloroacetic acid, furnished novel thiazolidin-4-one derivatives 7. Interestingly, carbothioamides 3, when treated with ethyl bromoacetate in the presence of triethylamine, furnished unexpected bis-compounds 9. The plausible route of formation of bis-compounds through a thioketene intermediate is supported by control experiments. The structures of new products were assigned by spectral, crystallographic, and DFT studies. Indazolyl-hydrazones 5 and indazolyl-hydrazono thiazolidin-4-ones 7 were examined for their in vitro anti-inflammatory activity utilizing lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Compounds 5c and 7c exhibited moderate anti-inflammatory efficacy by considerably lowering 68% and 74%, respectively of the expression of pro-inflammatory NO species compared to the budesonide positive control. Furthermore, compounds 5c and 7c exhibited considerable COX-2 inhibition with IC50 values of 72.15 μM and 68.39 μM, respectively, compared to the standard drug celecoxib (IC50 41.21 μM). Molecular docking studies supported the COX-2 inhibition by hydrazone 5c and thiazolidin-4-one derivative 7c with docking scores of −8.5 and −9.1 Kcal/mol, respectively, compared to celecoxib (−8.91 Kcal/mol).