Synthesis and anti-inflammatory activity evaluation of NO-releasing furoxan/1,2,4-triazole hybrid derivatives.

Sin-Min Li, Jia-Yu Chou, Shuo-En Tsai, Ching-Chun Tseng, Cheng-Yen Chung, Wei-Zheng Zeng, Yu-Pei Hu, Naoto Uramaru, Guan-Jhong Huang, Fung-Fuh Wong

European journal of medicinal chemistry 2023 Sep 05

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An efficient synthesis method was developed for furoxan/1,2,4-triazole hybrids 5a-k from methyl 5-(halomethyl)-1-aryl-1H-1,2,4-triazole-3-carboxylates 1 through two-steps reaction including hydrolyzation and esterification. All of the furoxan/1,2,4-triazole hybrid derivatives were characterized by spectroscopy. On the other hand, the influence of newly synthesized multi-substituted 1,2,4-triazoles on the exogenous NO release ability, in vitro and in vivo anti-inflammatory activity, and in silico predictions were experimentally evaluated. Based on the exogenous NO release ability study and SAR studies of in vitro anti-inflammatory activity, all of compounds 5a-k exhibited slightly NO release ability and potential anti-inflammatory activity on LPS-induced RAW264.7 cells (IC50 = 5.74-15.3 μM) compared to Celecoxib (IC50 = 16.5 μM) and Indomethacin (IC50 = 56.8 μM). Furthermore, compounds 5a-k were also subjected to in vitro COX-1/COX-2 inhibition assays. Particularly, compound 5f exhibited extraordinary COX-2 inhibition (IC50 = 0.0455 μM) and selectivity (SI = 209). In addition, compound 5f was also examined in vivo pro-inflammatory cytokine productions and gastric safety and possessed the better inhibition of cytokine and safety compared with Indomethacin at the same concentration. Through the molecular modeling and in silico physicochemical and pharmacokinetic properties prediction, compound 5f was stabilized in COX-2 active binding site and possessed the fundamental strong H-bond interaction with Arg499 to form the significant physicochemical and pharmacological properties as a candidate drug. Following the in vitro, in vivo, and in silico study results, compound 5f demonstrated to be a potential anti-inflammatory agent and had comparable effects with Celecoxib. Copyright © 2023 Elsevier Masson SAS. All rights reserved.

Citation

Sin-Min Li, Jia-Yu Chou, Shuo-En Tsai, Ching-Chun Tseng, Cheng-Yen Chung, Wei-Zheng Zeng, Yu-Pei Hu, Naoto Uramaru, Guan-Jhong Huang, Fung-Fuh Wong. Synthesis and anti-inflammatory activity evaluation of NO-releasing furoxan/1,2,4-triazole hybrid derivatives. European journal of medicinal chemistry. 2023 Sep 05;257:115496