期刊
BIOORGANIC CHEMISTRY
卷 112, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2021.104969
关键词
NN-disubstituted pyrrolidine-2; 5-dione; Cyclooxygenases; Lipoxygenase; Leukotriene; Carbonic anhydrase
资金
- Najran University, Ministry of Education, Kingdom of Saudi Arabia [NU/MID/17/222]
- Higher Education Commission (HEC) Pakistan [10562/KPK/RD/HEC/2017]
- HEC [5291/Federal/NRPU/RD/HEC/2016]
Dual inhibitors of COX and LOX for the management of inflammation were developed by structural modifications, resulting in two structurally diverse families. These synthesized derivatives displayed preferential COX-2 affinity and demonstrated appreciable in-vivo anti-inflammatory activity through various tests, with compound 78 emerging as the most active. Additionally, the involvement of various mediators in adjusting the inflammatory response was studied, and the biological results were rationalized by docking simulations.
Dual inhibition of the enzymatic pathways of cyclooxygenases (COX-1/COX-2) and lipoxygenase (LOX) is a rational approach for developing more efficient and safe anti-inflammatory agents. Herein, dual inhibitors of COX and LOX for the management of inflammation are reported. The structural modifications of starting pyrrolidine-2,5-dione aldehyde derivatives resulted in two structurally diverse families (Family A & B). Synthesized derivatives from both Families displayed preferential COX-2 affinity in submicromolar to nanomolar ranges. Disubstitution pattern of the most active series of compounds having N-(benzyl(4-methoxyphenyl)amino moiety presents a new template that is mimic to the diaryl pattern of traditional COX-2 inhibitors. Compound 78 with IC50 value of 0.051 +/- 0.001 mu M emerged as the most active compound. Highly potent COX-2/5-LOX inhibitors have also demonstrated appreciable in-vivo anti-inflammatory activity through carrageenan induced paw edema test. Moreover, the involvement of histamine, bradykinin, prostaglandin, and leukotriene mediators to adjust the inflammatory response were also studied. Apart from COX inhibition, sulfonamide is considered an important template for carbonic anhydrase inhibition. Hence, we also evaluated six sulfonamide derivatives for off-target in-vitro bovine carbonic anhydrase-II inhibition. Biological results were finally rationalized by docking simulations. Typically, most active COX-2 inhibitors interact with the amino acid residues responsible for the COX-2 selectivity.
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