Investigations on synthesis and structure elucidation of novel [1,2,4]triazolo[1,2-a]pyridazine-1-thiones and their inhibitory activity against inducible nitric oxide synthase

Abstract

The inducible nitric oxide synthase (iNOS) is a target of great research interest due to its importance in a number of diseases, for example, septic shock and inflammatory lung diseases. A variety of 3-substituted [1,2,4]triazolo[1,2-a]pyridazine derivatives was synthesized by ring closure with hexahydropyridazine-1-carbothioamide by using aliphatic and aromatic aldehydes. The activity of the new substances was tested on the insulin-secreting rat insulinoma cell line RINm5F. iNOS was expressed through exposure to interleukin-1β (IL-1β) and interferon-γ (IFN-γ). A number of the investigated compounds were more active than the reference inhibitor aminoguanidine (AG). Structure-activity relationships showed that a phenyl substituent in position 3 is apparently essential for inhibition.

Keywords: Hexahydropyridazine-1-carbothioamide; Inducible nitric oxide synthase; RINm5F; [1,2,4]Triazolo[1,2-a]pyridazine-1-thiones.