83676-82-8Relevant academic research and scientific papers
SAR studies on 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles as inhibitors of Mtb shikimate dehydrogenase for the development of novel antitubercular agents
Li, Ziqiang,Liu, Yishuang,Bai, Xiaoguang,Deng, Qi,Wang, Juxian,Zhang, Guoning,Xiao, Chunling,Mei, Yaning,Wang, Yucheng
, p. 97089 - 97101 (2015/12/01)
Shikimate dehydrogenase, an essential protein for the biosynthesis of the chorismate end product, is a highly promising therapeutic target, especially for the discovery and development of new-generation anti-TB agents. Following up the identification of one lead 3,6-disubstituted 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole (1), targeting Mt SD in our previous study, an extensive SAR study for optimization of the lead compound was performed through systematic modification of the 3 and 6 positions. This study has successfully led to the discovery of two highly potent advanced leads 6d-4, 6c-4 and several other compounds with comparable potencies (6d-4, MIC-H37Rv = 0.5 μg mL-1; MIC-MDRTB = 4.0 μg mL-1; MIC-RDRTB = 0.5 μg mL-1; Mt SD-IC50 = 14.20 μg mL-1; and 6c-4, MIC-H37Rv = 0.5 μg mL-1; MIC-MDRTB = 4.0 μg mL-1; MIC-RDRTB = 1.0 μg mL-1; Mt SD-IC50 = 6.82 μg mL-1). These advanced lead compounds possess a para-halogen phenyl at the 3 position. In vitro Mt SD inhibitory assay indicates that Mt SD is the target for their antitubercular activity. Moreover, the BacT/ALERT 3D liquid culture technology and in vitro Mt SD inhibitory assay were initially applied.
Novel lead structures for p38 MAP kinase via FieldScreen virtual screening
Cheeseright, Timothy J.,Holm, Melanie,Lehmann, Frank,Luik, Sabine,Gottert, Marcia,Melville, James L.,Laufer, Stefan
experimental part, p. 4200 - 4209 (2010/01/16)
p38 MAP kinase has received considerable interest in the pharmaceutical industry and remains a valid and interesting target for the treatment of inflammation. To discover novel p38 inhibitors, we applied the ligand-based virtual screening technique, FieldScreen, to 1.2 million commercially available compounds. Fifty-eight diverse compounds were selected for biological analysis, using molecular field similarity to known inhibitors, while explicitly removing any structure that shared a scaffold with previously reported p38 inhibitors. Of these, 11 (19%) showed ≥20% inhibition of p38 at 10 μM. We chose to prepare analogues of two distinct chemical series resulting in a potential lead compound with pIC50 of 6.4. Modeling of SAR using FieldAlign, a ligand alignment protocol, was used to rationalize the SAR of the series of thiadiazole based inhibitors.
