Chlorotrimethylsilane promoted one-flask heterocyclic synthesis of 1,2,4-triazoles from nitrilimines: Modeling studies and bioactivity evaluation of LH-21 and Rimonabant analogues.

An efficient one-flask cascade method for synthesis of the multi-substituted 1,2,4-triazoles via chlorotrimethylsilane as a promoter was developed. Firstly, nitrilimines were transformed to hydrazonamides as intermediate in high yield by treatment with commercially available hexamethyldisilazane. Subsequently, the mixture was added with corresponding acyl chloride and heated in the presence of pyridine to give the corresponding multi-substituted 1,2,4-triazoles via chlorotrimethylsilane promoted heterocyclization reaction. The utility of method was demonstrated to synthesize CB1 ligands including Rimonabant analogue 4c and LH-21 3 for modeling study. All synthesized compounds were subjected to the cAMP functional assay of CB1/CB2 receptor. Especially, compound 4g enhanced the reversal of cAMP reduction by CP59440 than LH-21 and Rimonabant analogue in CHO-hCB1 cells. In addition, the docking results showed compound 4g fits the best position with CB1 receptor. However, the ability to penetrate brain-blood barrier of compound 4g is similar with Rimonabant in MDCK-mdr1 permeability assay, which might cause CNS side effect. This study still provides the basis for further development of a potent and specific CB1 antagonist.