188564-63-8Relevant academic research and scientific papers
Syntheses and characterization of nimesulide derivatives for dual enzyme inhibitors of both cyclooxygenase-1/2 and 5-lipoxygenase
Li, Yue,Chen, Shu-Han,Ou, Tian-Miao,Tan, Jia-Heng,Li, Ding,Gu, Lian-Quan,Huang, Zhi-Shu
scheme or table, p. 2074 - 2083 (2011/05/05)
Cyclooxygenase-1/2 (COX-1/2) and 5-lipoxygenase (5-LOX) are enzymes in two different pathways in the inflammatory process. In the present study, a variety of new nimesulide derivatives were synthesized through incorporation of a 5-LOX pharmacophore into nimesulide followed with some structural modifications, which were then characterized for dual enzyme inhibitors for these two types of enzymes. Their structure-activity relationships (SARs) were studied, and compound 20f was found to be an excellent dual enzyme inhibitor. Its binding conformation and interaction mode were studied with molecular docking experiments. Compound 20f could become a lead compound for further development for potential anti-inflammatory drugs.
New aromatic inhibitors of EPSP synthase incorporating hydroxymalonates as novel 3-phosphate replacements
Shah, Ajit,Font, Jose L.,Miller, Michael J.,Ream, Joel E.,Walker, Mark C.,Sikorski, James A.
, p. 323 - 334 (2007/10/03)
A new, aromatic analogue of the EPSP synthase enzyme reaction intermediate 1 has been identified, which contains a 3-hydroxymalonate moiety in place of the usual 3-phosphate group. This simplified inhibitor was readily prepared in five steps from ethyl 3,4-dihydroxybenzoate. The resulting tetrahedral intermediate mimic 9 is an effective, competitive inhibitor versus S3P with an apparent K(i) of 0.57 ± 0.06 μM. This result demonstrates that 3-hydroxymalonates exhibit potencies comparable to aromatic inhibitors containing the previously identified 3-malonate ether replacements and can thus function as suitable 3-phosphate mimics in this system. These new compounds provide another example in which a simple benzene ring can be used effectively in place of the more complex shikimate ring in the design of EPSP synthase inhibitors. Furthermore, the greater potency of 9 versus the glycolate derivative 10 and the 5-deoxy analog 11, again confirms the requirement for multiple anionic charges at the dihydroxybenzoate 5-position in order to attain effective inhibition of this enzyme.
