Abstract:
:Dual inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO), two key enzymes involved in pro-inflammatory eicosanoid biosynthesis, represents a new strategy for treating inflammatory disorders. Herein we report the discovery of 2,4-thiazolidinedione-based mPGES-1/5-LO dual inhibitors following a multidisciplinary protocol, involving virtual combinatorial screening, chemical synthesis, and validation of the biological activities for the selected compounds. Following the multicomponent-based chemical route for the decoration of the 2,4-thiazolidinedione core, a large library of virtual compounds was built (∼2.0×104 items) and submitted to virtual screening. Nine selected molecules were synthesized and biologically evaluated, disclosing among them four compounds able to reduce the activity of both enzymes in the mid- and low- micromolar range of activities. These results are of interest for further expanding the chemical diversity around the 2,4-thiazolidinedione central core, facilitating the identification of novel anti-inflammatory agents endowed with a promising and safer pharmacological profile.
journal_name
ChemMedChemjournal_title
ChemMedChemauthors
Lauro G,Terracciano S,Cantone V,Ruggiero D,Fischer K,Pace S,Werz O,Bruno I,Bifulco Gdoi
10.1002/cmdc.201900694subject
Has Abstractpub_date
2020-03-18 00:00:00pages
481-489issue
6eissn
1860-7179issn
1860-7187journal_volume
15pub_type
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