Design, synthesis and biological evaluation of new 2,3-diarylquinoline derivatives as selective cyclooxygenase-2 inhibitors

Ghodsi, Razieh; Zarghi, Afshin; Daraei, Bahram; Hedayati, Mehdi

doi:10.1016/j.bmc.2009.12.060

Cited by 50 publications

(36 citation statements)

References 23 publications

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“…27-34 Consistent with this observation, the 2-furylquinoline-4-carbonyl substructure is present in 170 HTS library members available in the University of Minnesota and the NIH MLPCN screening libraries and in many of our own HTS hits (Figure 1). As a result of marked A3 inhibition in HTS screening, a low toxicity profile against human cells, and the lack of PAINS warnings, we initiated a structural optimization campaign to refine 1 for potency and selectivity.…”

Section: Introductionsupporting

confidence: 71%

Oxidative Reactivities of 2-Furylquinolines: Ubiquitous Scaffolds in Common High-Throughput Screening Libraries

et al. 2015

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High-throughput screening (HTS) was employed to discover APOBEC3G inhibitors and multiple 2-furylquinolines (e.g., 1) were found. Dose-response assays with 1 from the HTS sample, as well as commercial material, yielded similar confirmatory results. Interestingly, freshly synthesized and DMSO-solubilized 1 was inactive. Repeated screening of the DMSO aliquot of synthesized 1 revealed increasing APOBEC3G inhibitory activity with age, suggesting 1 decomposes into an active inhibitor. Laboratory aging of 1 followed by analysis revealed that 1 undergoes oxidative decomposition in air, resulting from a [4+2] cycloaddition between the furan of 1 and 1O2. The resulting endoperoxide then undergoes additional transformations, highlighted by Baeyer-Villager rearrangements, to deliver lactam, carboxylic acid, and aldehyde products. The endoperoxide also undergoes hydrolytic opening followed by further transformations to a bis-enone. Eight structurally related analogues from HTS libraries were similarly reactive. This study constitutes a cautionary to validate 2-furylquinolines for structure and stability prior to chemical optimization campaigns.

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Section: Introductionsupporting

confidence: 71%

Oxidative Reactivities of 2-Furylquinolines: Ubiquitous Scaffolds in Common High-Throughput Screening Libraries

et al. 2015

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“…In contrast with the traditional NSAIDs which belong to different categories of chemical structures, selective COX-2 inhibitors can be classified into three groups ( Figure 1): (1) diaryl ethers with methanesulfonamide at position-2 of one ring, Nemisulide and CGP-28237 can be considered as lead compounds in this class 8 ; (2) trans-stilbenoids, such as resveratrol, a natural product found in grapes and other food products 9 ; (3) heterocyclic systems (such as 1,2,4 triazole 10,11 , imidazole 12 , pyrazol 13 , quinoline 14 , indol 15 , pyrimidine 16 , 1,2,4-triazine 17,18 ) with adjacent diaryl containing sulfamoyl (SO 2 NH 2 ) or methylsulfonyl (SO 2 Me) substitution at position-4 of one ring which exist in celecoxib, SC-558 and etoricoxib.…”

Section: Introductionmentioning

confidence: 99%

Structure-based design, synthesis, molecular docking study and biological evaluation of 1,2,4-triazine derivatives acting as COX/15-LOX inhibitors with anti-oxidant activities

Khoshneviszadeh

Shahraki

Khoshneviszadeh

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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A set of 1,2,4-triazine derivatives were designed as cyclooxygenase-2 (COX-2) inhibitors. These compounds were synthesized and screened for inhibition of cyclooxygenases (COX-1 and COX-2) based on a cellular assay using human whole blood (HWB) and lipoxygenase (LOX-15) that are key enzymes in inFammation. The results showed that 3-(2-(benzo-bis(4-methoxyphenyl)-1,2,4-triazine (G11) was identified as the most potent COX-2 inhibitor (78%) relative to COX-1 (50%). Ferric reducing anti-oxidant power (FRAP) assay revealed that compound G10 possesses the highest anti-oxidant activity. The compound G3 with IC 50 value of 124 mM was the most potent compound in LOX inhibitory assay. Molecular docking was performed and a good agreement was observed between computational and experimental results.

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“…Recent studies have also shown that selective COX-2 inhibitors may slow the progress of Alzheimer's disease without causing gastrointestinal damage (Nivsarkar et al, 2008). 1,2-Diarylheterocycles have been extensively studied as selective COX-2 inhibitors (Ghodsi et al, 2010;Penning et al,1997;Prasit et al, 1999;Riendeau et al, 2002;Navidpour et al, 2006;Salimi et al, 2007;Zarghi et al, 2009). All these tricyclic molecules possess 1,2-diaryl substitution on a central hetero or carbocyclic ring system (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we reported a group of new diarylheterocyclic COX-2 inhibitors possessing a bicyclic central ring which exhibited highly selectivity for COX-2 inhibition. (Ghodsi et al, 2010;Zarghi et al, 2009). As part of our ongoing program to design new types of tricyclic selective COX-2 inhibitors, we now report the design, synthesis, cyclooxygenase inhibitory, and some molecular modeling studies of a new group of 1,2-diarylheterocycles possessing a 4,5,6,7-tetrahydro-1H-benzo[d]imidazole central ring and a COX-2 SO 2 Me pharmacophore at the para-position of C-2 phenyl ring.…”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of new 1,2-diaryl-4,5,6,7-tetrahydro-1H-benzo[d] imidazoles as selective cyclooxygenase (COX-2) inhibitors

et al. 2011

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A new series of 1,2-diaryl-4,5,6,7-tetrahydro-1H-benzo [d]imidazoles, possessing a methylsulfonyl pharmacophore, were synthesized to evaluate their biological activities as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 isozyme inhibition studies were carried out to acquire structure-activity relationship data with respect to the point that molecular modeling studies showed that designed compounds bind in the primary binding site such that the SO 2 Me substituent at para-position of C-2 phenyl ring inserts into the 2°pocket present in COX-2 enzyme. COX-1 and COX-2 inhibition studies showed that all compounds were selective inhibitors of the COX-2 isozyme with IC 50 values in the highly potent 0.34-0.69 lM range, and COX-2 selectivity indexes in the 52.3-163.8 range. 1-(4-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4,5,6,7-tetrahydro-1H-benzo[d] imidazole was identified as the most potent (IC 50 = 0.34 lM), and selective (SI = 163.8), COX-2 inhibitor among the synthesized compounds.

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Design, synthesis and biological evaluation of new 2,3-diarylquinoline derivatives as selective cyclooxygenase-2 inhibitors

Cited by 50 publications

References 23 publications

Oxidative Reactivities of 2-Furylquinolines: Ubiquitous Scaffolds in Common High-Throughput Screening Libraries

Oxidative Reactivities of 2-Furylquinolines: Ubiquitous Scaffolds in Common High-Throughput Screening Libraries

Structure-based design, synthesis, molecular docking study and biological evaluation of 1,2,4-triazine derivatives acting as COX/15-LOX inhibitors with anti-oxidant activities

Design and synthesis of new 1,2-diaryl-4,5,6,7-tetrahydro-1H-benzo[d] imidazoles as selective cyclooxygenase (COX-2) inhibitors

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