Spectral and Crystallographic Study of Pyridinic Analogues of Nimesulide: Determination of the Active Form of Methanesulfonamides as COX-2 Selective Inhibitors

Julémont, Fabien; Leval, Xavier de; Michaux, Catherine; Damas, Jacques; Charlier, Caroline; Durant, François; Pirotte, Bernard; Dogné, Jean‐Michel

doi:10.1021/jm020920n

Cited by 35 publications

(44 citation statements)

References 13 publications

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“…At the physiological pH of 7.4, arylacetic and phenyl acid compounds are expected to exist as negatively charged species with an anionic carboxylate moiety and nimesulide with an anionic sulphonamidate (87.0%) [13]. The presence of several functional groups with acidbase properties confers an amphoteric character to isoxicam.…”

Section: Methodsmentioning

confidence: 99%

“…Indeed, if the oxygen replaces the nitrogen in the indolic ring, the antioxidant activity of the resulting benzofurane is 40% lower [26 -28]. Delocalization of this electron pair over the aromatic system seems to be of great importance for its antioxidant activity [13,29,30], which may explain the lack of effect found for diclofenac and zomepirac against O 2 .À , since the structural feature that distinguishes diclofenac and zomepirac from indomethacine and nimesulide is the absence of electronic delocalization (Figure 4a), which decreases their ability for substitution on the aromatic rings and therefore the consequent reactivity. The activating effect of the methoxyl group in the indolic aromatic ring may also contribute to this effect.…”

Section: No Yetmentioning

confidence: 99%

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Reactivity of Biologically Important NSAID Compounds with Superoxide (O₂^.−), nitric oxide (^.NO) and Cyclooxygenase Inhibition

et al. 2007

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In the present study, we investigated the free radical-scavenging effects of eight Nonsteroidal Anti-Inflammatory Drugs (NSAID) using a Superoxide (O 2 .À ) and Nitric Oxide ( . NO) generating system in vitro. Indomethacine showed higher scavenging activity against O 2 .À , it being more potent than ibuprofen and nimesulide at the same concentration. Diclofenac showed a more relevant effect on the .NO scavenging activity than against O 2 .À . Comparison of the activities of eight compounds showed that the aryl-acetic compounds have higher scavenging activities than the diarylheterocyclic ones. We have also found that the O 2 scavenging activity correlates with the Next-Highest-Occupied pOrbital (NHOMO) levels and the Next-Lowest-Unoccupied p-Orbital (NLUMO)-NHOMO gaps correlate with Cyclooxygenase-1 (COX-1) inhibitory activity. These results suggest that both NHOMO and NHOMO-NLUMO gap energies can be of predictive value in the search for new candidate anti-inflammatory drugs.

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Section: Methodsmentioning

confidence: 99%

Section: No Yetmentioning

confidence: 99%

Reactivity of Biologically Important NSAID Compounds with Superoxide (O₂^.−), nitric oxide (^.NO) and Cyclooxygenase Inhibition

et al. 2007

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“…1) Zhong et al, 2011;Su et al, 2008) and SKBR-3 breast cancer cell growth is inhibited by it with an IC 50 which is more active than nimesulide about 100 folds. The potential COX-2 activity is abolished by the N-methylation of JCC76 which blocks the ionization of its sulfonamide group (Su et al, 2006;Renard et al, 2006;Julemont et al, 2002). Due to the multistep nitroreductive bioactivation, nimesulide shows hepatotoxicity that produces the hazardous nitroanion radical and nitroso intermediate.…”

Section: Introductionmentioning

confidence: 99%

Atom-based QSAR and 3D QSAR using pharmacophore based alignment for discovery of nimesulide-derived SKBR-3 cell line inhibitors

Choudhury

2014

Med Chem Res

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Growth suppression of many non-COX-2 expressing tumor cells can be exhibited by COX-2 inhibitors, where supplementation of cells with exogenous prostaglandins fails to rescue the cells from growth inhibition. It can, therefore, be speculated that anti-cancer properties of some COX-2 inhibitors may be contributed by the COX-2-independent effects also. Some of the derivatives obtained from certain COX-2 inhibitors which show non-COX-2 inhibitory mechanism have revealed some significant anti-cancer activities. From a COX-2 selective inhibitor nimesulide, an analog JCC76 is derived which is a non-COX-2 active compound and shows inhibition of SKBR-3 breast cancer cell growth. Other JCC76 derived inhibitors also played significant role in SKBR-3 cell inhibition. An analog-based study was done using pharmacophore modeling and 3D-QSAR to provide clues for potential lead compound designing. A five point pharmacophore ADHRR was generated using 39 JCC76-derived SKBR-3 inhibitors. The validated pharmacophore alignment was used for further 3D-QSAR analysis, which presented a good R 2 value of 0.562, 0.982, and 0.848 for atombased QSAR, CoMFA, and CoMSIA model, respectively. All the QSAR models presented good statistical significance and predictivity. The corresponding Q 2 values for each model are 0.513, 0.649, and 0.518, respectively. Both the pharmacophore and CoMSIA results displayed that the H-bond donor and acceptor sites are the key structural feature for JCC76-derived non-COX-2-dependent inhibitors with high activity.

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“…The functionality at the B position is very critical for the COX-2 inhibitory activity ( Figure 1). 27 Only when the N-H is available in the ionized form, do the compounds inhibit COX-2. Introduction of any group in B position eliminates this ionization process and produce compounds with no COX-2 inhibitory activity.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Novel Sulfonanilide Compounds as Antiproliferative Agents for Breast Cancer

Darby

Brueggemeier

2008

J. Comb. Chem.

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Combinatorial chemistry approaches facilitate drug discovery processes and result in structural modifications of lead compounds that enhance pharmacological activity, improve pharmacokinetic properties, and/or reduce unwanted side effects. Epidemiological and animal model studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) can act as chemopreventive agents. The cyclooxygenase-2 (COX-2) inhibitor nimesulide shows anticancer effect in several cancer cell lines via COX-2 dependent and independent mechanisms. The molecular structure of nimesulide was used as a starting scaffold to design novel sulfonanilide analogs and examine the structural features that contribute to this anticancer effect. A systematic combinatorial chemical approach was used to generate diversely substituted sulfonanilide derivatives that were tested for their effects on the proliferation of human breast cancer cells. Structure-function analysis indicated that the inhibition of cell growth by compounds derived from the novel sulfonanilides required a bulky terminal phenyl ring, a methanesulfonamide, and a hydrophobic carboxamide moiety.

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Spectral and Crystallographic Study of Pyridinic Analogues of Nimesulide: Determination of the Active Form of Methanesulfonamides as COX-2 Selective Inhibitors

Cited by 35 publications

References 13 publications

Reactivity of Biologically Important NSAID Compounds with Superoxide (O₂^.−), nitric oxide (^.NO) and Cyclooxygenase Inhibition

Reactivity of Biologically Important NSAID Compounds with Superoxide (O₂^.−), nitric oxide (^.NO) and Cyclooxygenase Inhibition

Atom-based QSAR and 3D QSAR using pharmacophore based alignment for discovery of nimesulide-derived SKBR-3 cell line inhibitors

Synthesis and Biological Evaluation of Novel Sulfonanilide Compounds as Antiproliferative Agents for Breast Cancer

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Spectral and Crystallographic Study of Pyridinic Analogues of Nimesulide: Determination of the Active Form of Methanesulfonamides as COX-2 Selective Inhibitors

Cited by 35 publications

References 13 publications

Reactivity of Biologically Important NSAID Compounds with Superoxide (O2.−), nitric oxide (.NO) and Cyclooxygenase Inhibition

Reactivity of Biologically Important NSAID Compounds with Superoxide (O2.−), nitric oxide (.NO) and Cyclooxygenase Inhibition

Atom-based QSAR and 3D QSAR using pharmacophore based alignment for discovery of nimesulide-derived SKBR-3 cell line inhibitors

Synthesis and Biological Evaluation of Novel Sulfonanilide Compounds as Antiproliferative Agents for Breast Cancer

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Product

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Reactivity of Biologically Important NSAID Compounds with Superoxide (O₂^.−), nitric oxide (^.NO) and Cyclooxygenase Inhibition

Reactivity of Biologically Important NSAID Compounds with Superoxide (O₂^.−), nitric oxide (^.NO) and Cyclooxygenase Inhibition