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

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

  • Bioorg Chem. 2020 Nov;104:104299. doi: 10.1016/j.bioorg.2020.104299.
Shuo-En Tsai 1,  Sin-Min Li 2,  Ching-Chun Tseng 1,  Cheng-Yen Chung 1,  Yu-Hui Zeng 3,  Chun Chieh Lin 4,  Mao-Tsu Fuh 5,  Li-Chan Yang 4,  Ya-Chen Yang 6,  Fung-Fuh Wong 7
Affiliations

Affiliations

  • 1 School of Pharmacy, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan; Ph.D. Program for Biotech Pharmaceutical Industry, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan.
  • 2 Institute of New Drug Development, China Medical University, No. 91 Hsueh-Shih Rd., Taichung 40402, Taiwan.
  • 3 Master Program for Pharmaceutical Manufacture, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan.
  • 4 School of Pharmacy, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan.
  • 5 Division of Metabolism, Department of Internal Medicine, China Medical University, Taichung 40402, Taiwan.
  • 6 Department of Food Nutrition and Health Biotechnology, Asia University, No. 500, Liufeng Rd., Wufeng Dist., Taichung City 413, Taiwan.
  • 7 School of Pharmacy, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan. Electronic address: [email protected].
PMID: 33002729 DOI: 10.1016/j.bioorg.2020.104299
Abstract

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.

Keywords

1, 2, 4-Triazole; CB(1) ligand; Chlorotrimethylsilane; Heterocyclization; Nitrilimines; Rimonabant.

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