Computer-Aided Discovery of Anti-Inflammatory Thiazolidinones with Dual Cyclooxygenase/Lipoxygenase Inhibition

Abstract

New anti-inflammatory agents possessing dual cyclooxygenase/lipoxygenase (COX/LOX) inhibition were discovered by computer-aided prediction of biological activity for 573 virtually designed chemical compounds. Prediction of biological activity was performed by PASS, and prediction results were analyzed with PharmaExpert software. Nine 2-(thiazole-2-ylamino)-5-phenylidene-4-thiazolidinone derivatives differing by the phenyl group substitution were selected for synthesis and experimental testing as potential COX/LOX inhibitors. Eight tested compounds exhibited anti-inflammatory activity in the carrageenin-induced paw edema. It was shown that seven tested compounds (77.8%) were LOX inhibitors, seven compounds were COX inhibitors (77.8%), and six tested compounds (66.7%) were dual COX/LOX inhibitors. Analysis of lipophilicity of the compounds showed a negative correlation with inhibition of edema formation. The binding modes of the most active compounds of this series (2-(thiazole-2-ylamino)-5-( m-chlorophenylidene)-4-thiazolidinone for COX-1 and COX-2, and 2-(thiazole-2-ylamino)-5-( m-nitrophenylidene)-4-thiazolidinone for 15-LOX) were proposed on the basis of docking studies.

N-substituted [phenyl-pyrazolo]-oxazin-2-thiones as COX-LOX inhibitors: influence of the replacement of the oxo -group with thioxo- group on the COX inhibition activity of N-substituted pyrazolo-oxazin-2-ones

“…The prostanoid product is quantified via enzyme immunoassay using a broadly specific antibody that binds to all the major prostaglandin compounds. 5,9 The inhibitory activity of the compounds was tested at arachidonic acid concentration of 1 μΜ. The compounds were added at the reaction mixture at a final concentration of 200 μΜ for a first screening of inhibitory action.…”

“…Thus, many researchers focused on the development of dual acting COX/LOX inhibitors. 1,2,5 It has been stated that a balanced modulation of several targets can provide superior therapeutic effects and a favorable side effect profile compared to the action of a selective ligand, particularly in cases of complex diseases. 6 Licofelone, a COX-2/5-LOX inhibitor, has been evaluated in a phase III clinical trial.…”

“…Ziakas et al 9 tested a number of tolfenamic and BHT derivatives and Geronikaki et al tested novel thiazolidinone derivatives for COX-1, COX-2 and LOX inhibition. 5 Oxazinones and pyrazole derivatives attracted organic chemists due to their biological and chemotherapeutic importance. Several benzo-oxazinones and related fused heterocycles are of interest as potential bioactive molecules.…”

Synthesis, Characterization and Biological Evaluation of Some Benzothiazole Derivatives as Potential Antimicrobial Agent.

“…They are also useful as anti-allergic 13 , anti-inflammatory 14 and anthelmintic 15 agents and as appetite depressants 16 , intermediates for dyes 17 , plant protectants 18 , histamine H2antagonists 19 and photographic sensitizers 20 . On the other hand, careful literature survey revealed that thiazole, thiophene and pyrazole ring systems have occupied a unique position in the design and synthesis of novel biological active agents with remarkable analgesic and antiinflammatory activities [21][22][23] , in addition to their well documented potential antimicrobial activities [24][25][26][27] . Morever, thiazoles have found application in drug development for the treatment of hypertension 28 , schizophrenia 29 , HIV infections 30 , and as new inhibitors of bacterial DNA gyrase B 31 .…”

Synthesis and Evaluation of New 2-Iminothiazolidin-4-one and Thiazolidin-2,4-dione Derivatives as Antimicrobial and Anti-inflammatory Agents

“…Their different biological activities were reported [1,2]. Among the most important biological and pharmacological activities of both heterocyclic pharmacophoric moieties are: antihyperglycemic [3,4], antibacterial [5][6][7][8][9], antifungal [10,11], antiinflammatory [12][13][14][15][16][17], cyclooxygenase and lipoxygenase inhibitors [18,19], anticonvulsants [20,21], antitumor [22], antioxidant [23] and several other activities [1,2].…”