title: Synthesis and structure elucidation of 2,3,5,6,7,8-hexahydro-1 H-[1,2,4]triazolo[1,2-a]pyridazine-1-thione, 3,3-disubstituted and 2-substituted derivatives and evaluation of their inhibitory activity against inducible nitric oxide synthase.
abstract: The 3-monosubstituted 2,3,5,6,7,8-hexahydro-1 H-[1,2,4]triazolo[1,2-a]pyridazine-1-thiones 3 (R1, R3 = H) were recently reported to possess inhibitory activity against inducible nitric oxide synthase in a cell based assay (Schulz et al. 2013). The 3,3-disubstituted 2,3,5,6,7,8-hexahydro-1H-[1,2,4]triazolo[1,2-a]pyridazine-1-thiones 3 and 4 (R2,R3 ≠ H) were synthesized by cyclocondensation of the hexahydropyridazine-1-carbothioamides 1 with ketones. In order to access the 3,3-unsubstituted 2,3,5,6,7,8-hexahydro-1H-[1,2,4]triazolo[1,2-a]pyridazine-1-thiones, the unsubstituted parent system of these compounds, several synthetic routes were studied. By these methods the desired heterocyclic system 2a as well as new a-anellated and N-substutited hexahydropyridazines were obtained. The biological evaluation of the title compounds confirmed the previously made finding that an aromatic moiety in position 3 of the substance is important for an inducible nitric oxide synthase (iNOS) inhibitory activity.
authors.forename: U
authors.initials: U
authors.lastname: Schulz
authors.forename: M
authors.initials: M
authors.lastname: Freitag
authors.forename: K
authors.initials: K
authors.lastname: Schmidt
authors.forename: M
authors.initials: M
authors.lastname: Witetschek
authors.forename: M
authors.initials: M
authors.lastname: Polzin
authors.forename: O
authors.initials: O
authors.lastname: Morgenstern
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D008958:Models, Molecular; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013871:Thiones / Q000138:chemical synthesis* / Q000494:pharmacology*; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: C000598368:2,3,5,6,7,8-hexahydro-1H-(1,2,4)triazolo(1,2-a)pyridazine-1-thione; D004791:Enzyme Inhibitors; D011724:Pyridazines; D013871:Thiones; D014230:Triazoles; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II