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A series of 6-nitro-3-(m-tolylamino) benzo[d]isothiazole 1,1-dioxide analogues were synthesized and evaluated for their inhibition activity against 5-lipoxygenase (5-LOX) and microsomal prostaglandin E2 synthase (mPGES-1). These compounds can inhibit both enzymes with IC50 values ranging from 0.15 to 23.6μM. One of the most potential compounds, 3g, inhibits 5-LOX and mPGES-1 with IC50 values of 0.6μM, 2.1μM, respectively., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The arachidonic acid (AA) metabolic network produces key inflammatory mediators which have been considered as hallmark contributors in various inflammatory related diseases. Enzymes in this network, such as 5-lipoxygenase (5-LOX), cyclooxygenase (COX), leukotriene A(4) hydrolase (LTA4H) and prostaglandin E synthase (PGES), have been used as targets for anti-inflammatory drug discovery. Multi-target drugs and drug combinations have also been developed for this network. However, how the inhibitors alter the dynamics of metabolite production and which combinatorial target intervention solutions are better needs further exploration. We did a system based intervention analysis on the AA metabolic network. Using an LC-MS/MS method, we quantitatively studied the eicosanoid metabolites responses of AA metabolic network during stimulation of Sprague Dawley rat blood samples with the calcium ionophore. Our results indicate that inhibiting the upstream rather than the downstream target of 5-LOX pathway will simultaneously alter the AA metabolism to the COX pathway (and vice versa). Therefore, single-target inhibitors cannot control all the inflammatory mediators at the same time. We also suggest that in the case of multiple-target anti-inflammatory solutions, the combination of inhibitors of the downstream enzymes may have stronger inhibition efficiency and cause less side-effects compared to the other solutions. One therapeutic strategy, LTA4H/COX inhibition solution, was found promising for the intervention of inflammatory mediator biosynthesis and at the same time stimulating the production of anti-inflammatory agents.

A series of novel fused heterocycle methyl esters were designed and synthesized as human nonpancreatic secretory phospholipase A₂ (hnps-PLA₂) competitive inhibitors. Among the 22 synthesized compounds, 17 quinoline-4-methyl esters displayed hnps-PLA₂ inhibition activity in the in vitro bioassay. The IC₅₀ value for the best compound 3o was 1.5 μM. The structure-inhibition-activity relationships of the compounds were studied using molecular docking., (Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.)

Dual target inhibitors against COX-2 and LTA(4)H were designed by adding functional groups from a marketed COX-2 inhibitor, Nimesulide, to an existing LTA(4)H inhibitor 1-(2-(4-phenoxyphenoxy) ethyl) pyrrolidine. A series of phenoxyphenyl pyrrolidine compounds were synthesized and tested for their inhibition activities using enzyme assays and human whole blood assay. Introduction of small electron withdrawing groups like NO(2) and CF(3) in the ortho-position of the terminal phenyl ring was found to change the original single target LTA(4)H inhibitor to dual target LTA(4)H and COX-2 inhibitors. Compound 5a and 5m showed dual LTA(4)H and COX-2 inhibition activities in the enzyme assays and the HWB assay with IC(50) values in the micromolar to submicromolar range. As their activities in HWB assay were comparable to the two starting single target inhibitors, the two compounds are promising for further studies. The strategy used in the current study may be generally applicable to other dual target drug designs.

Human 5-lipoxygenase (5-LOX) is one of the key anti-inflammatorydrug targets due to its key role in leukotrienes biosynthesis. Wehave built a model for the active conformation of human 5-LOX usingcomparative modeling, docking of known inhibitors, and molecular dynamicssimulation. Using this model, novel 5-LOX inhibitors were identifiedby virtual screen. Of the 105 compounds tested in a cell-free assay,30 have IC50values less than 100 μM and 11 lessthan 10 μM with the strongest inhibition of 620 nM. Compounds 4, 7, and 11showed strong inhibitionactivity in the human whole blood (HWB) assay with IC50values of 8.6, 9.7, 8.1 μM, respectively. Moreover, compounds 4and 7were also found to inhibit microsomalprostaglandin E synthase (mPGES)-1 with micromolar IC50values, similar to licofelone, a dual functional inhibitor of 5-LOX/mPGES-1.The compounds reported here provide new scaffolds for anti-inflammatorydrug design. [ABSTRACT FROM AUTHOR]

Abstract: A series of novel fused heterocycle methyl esters were designed and synthesized as human nonpancreatic secretory phospholipase A2 (hnps-PLA2) competitive inhibitors. Among the 22 synthesized compounds, 17 quinoline-4-methyl esters displayed hnps-PLA2 inhibition activity in the in vitro bioassay. The IC50 value for the best compound 3o was 1.5μM. The structure-inhibition–activity relationships of the compounds were studied using molecular docking. [Copyright &y& Elsevier]

Abstract: Human 5-lipoxygenase (5-LOX) is a well-validated target for anti-inflammatory therapy. Development of novel 5-LOX inhibitors with higher activities is highly demanded. In previous study, we have built a model for the active conformation of human 5-LOX, and identified naphthalen-1-yl 3,5-dinitrobenzoate (JMC-4) as a 5-LOX inhibitor by virtual screening. In the present work, 3,5-dinitrobenzoate-based 5-lipoxygenase inhibitors were developed. Twenty aryl 3,5-dinitrobenzoates, N-aryl 3,5-dinitrobenzamides and analogues were designed and synthesized. Several of them were found with significantly increased activities according to cell-free assay and human whole blood assay. The structure–activity relationship study may provide useful insights for designing effective 5-LOX inhibitors. [Copyright &y& Elsevier]