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  3. New methyl 5-(halomethyl)-1-aryl-1H-1,2,4-triazole-3-carboxylates as selective COX-2 inhibitors and anti-inflammatory agents: Design, synthesis, biological evaluation, and docking study

New methyl 5-(halomethyl)-1-aryl-1H-1,2,4-triazole-3-carboxylates as selective COX-2 inhibitors and anti-inflammatory agents: Design, synthesis, biological evaluation, and docking study

  • Bioorg Chem. 2020 Nov;104:104333. doi: 10.1016/j.bioorg.2020.104333.
Sin-Min Li 1,  Shuo-En Tsai 2,  Chia-Yin Chiang 2,  Cheng-Yen Chung 3,  Tsung-Jui Chuang 4,  Ching-Chun Tseng 2,  Wen-Ping Jiang 5,  Guan-Jhong Huang 5,  Chin-Yu Lin 1,  Ya-Chen Yang 6,  Mao-Tsu Fuh 7,  Fung-Fuh Wong 8
Affiliations

Affiliations

  • 1 Institute of New Drug Development, China Medical University, No. 91 Hsueh-Shih Rd., Taichung 40402, Taiwan.
  • 2 Ph.D. Program for Biotech Pharmaceutical Industry, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan.
  • 3 Ph.D. Program for Biotech Pharmaceutical Industry, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan; School of Pharmacy, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan.
  • 4 Master Program for Pharmaceutical Manufacture, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan.
  • 5 Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan.
  • 6 Department of Food Nutrition and Health Biotechnology, Asia University, Taichung 41354, Taiwan.
  • 7 Division of Metabolism, Department of Internal Medicine, China Medical University, Taichung 40402, Taiwan.
  • 8 Ph.D. Program for Biotech Pharmaceutical Industry, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan; School of Pharmacy, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan. Electronic address: [email protected].
PMID: 33142408 DOI: 10.1016/j.bioorg.2020.104333
Abstract

A new method was developed for synthesis of 1,2,4-triazole-3-carboxylates 5a-p and 6 from nitrilimines 3a-p through amination and heterocyclization two-steps reactions. All of 1,2,4-triazole-3-carboxylates 5 and 6 were characterized by spectroscopy technique. Based on the SAR study of anti-inflammation activity, most of these compounds showed potential anti-inflammatory activity on NO inhibition in LPS-induced RAW 264.7 cells (IC50 < 7.0 µM) compared with Celecoxib and Indomethacin. Several potential compounds 5b-h, 5j, 5l, 5n, and 5o were subjected to in vitro cyclooxygenase COX-1/COX-2 inhibition assays. Compound 5d showed extraordinary COX-2 inhibition (IC50 = 17.9 nM) and the best selectivity (COX-1/COX-2 = 1080). Furthermore, 5 mg/kg compound 5d exhibited better in vivo anti-inflammation and gastric protection results compared to 10 mg/kg Indomethacin. Docking experiments of 5d into COX-2 binding pocket have been evaluated. Following the bioactivities experimental data, the potential drug candidate 5d, significantly exhibited better anti-inflammatory effect than Indomethacin.

Keywords

1,2,4-Triazole; Anti-inflammation; COX-2 inhibitor; Heterocyclization.

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