Synthesis and Evaluation of a Novel Series of Pyrrolizine Derivatives as Dual Cyclooxygenase‐1 and 5‐Lipoxygenase Inhibitors

Laufer, Stefan; Striegel, Hans-Günter; Neher, Karola; Zechmeister, P.; Donat, C.; Stolingwa, Katrin; Baur, S.; Tries, S.; Kammermeier, T.; Dannhardt, Gerd; Kiefer, Werner

doi:10.1002/ardp.19973300908

Cited by 26 publications

(17 citation statements)

References 25 publications

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“…The same conditions led to the 3-chloro derivative (14) in 15% yield. When the reaction was applied to the thienyl compound (8) a mixture of two derivatives was obtained.…”

Section: Introductionmentioning

confidence: 76%

“…The 3-amino-6-chloro-4-and 5-methylpyridazines were synthesized according to previously described method leading to a 1:10 mixture of unseparable isomers [11]. The bromoketones were commercially available with the exception of 2-bromoacetylthiophene, 2-bromoacetyl-5-chlorothiophene and 2-bromoacetylfuran which were prepared according to previously reported methods [12][13][14].…”

Section: Experimental General Detailsmentioning

confidence: 99%

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Reactivity of 2‐substituted imidazo[1,2‐b]pyridazines: Preparation of 3‐nitro, nitroso and chloro derivatives

Hervet

Galtier

Enguehard

et al. 2002

Journal of Heterocyclic Chem

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The synthesis of 2‐substitutedimidazo[1,2‐b]pyridazines and their reactivity towards electrophilic substitutions are reported. The nitration was shown to be very dependent on the nature of the 2 substituent. Nitrosation using sodium nitrite in acetic acid media as a general method failed in all cases whereas chlorination was observed in warm hydrochloric acid. In order to ascertain the structure of some chloro derivatives, chlorination using N‐chlorosuccinimide was also reported. Depending of the nature of the substituent, the reaction occurred at the C‐3 imidazolic position and/or at the substituent on position 2. The 3‐nitroso‐2‐phenyl derivative was finally obtained using an alternative synthetic pathway by direct condensation of 3‐amino‐6‐chloropyridazine to ω‐chloro‐ω‐nitrosoacetophenone. The structural determinations were ascertained using high field lH and 13C‐NMR.

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“…The same conditions led to the 3-chloro derivative (14) in 15% yield. When the reaction was applied to the thienyl compound (8) a mixture of two derivatives was obtained.…”

Section: Introductionmentioning

confidence: 76%

Section: Experimental General Detailsmentioning

confidence: 99%

Reactivity of 2‐substituted imidazo[1,2‐b]pyridazines: Preparation of 3‐nitro, nitroso and chloro derivatives

Hervet

Galtier

Enguehard

et al. 2002

Journal of Heterocyclic Chem

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“…Preparation of the COX-1, COX-2, and 5-LOX Protein and Ligands (12)(13)(14)(15)(16)(17)(18)(19) The protein structures were handled by using Accelrys Discovery Studio Visualize v4.1 software (Accelrys Inc., San Diego, CA, USA (2005)). The crystal structures of proteins were retrieved from Protein Data Bank (http://www.rscb.…”

Section: Molecular Docking Studymentioning

confidence: 99%

“…All water molecules were removed because the extra water molecules will mask the protein surface from the ligand. The three-dimensional structures (pdb format) of the ligands (12)(13)(14)(15)(16)(17)(18)(19) were constructed using Chem3D Ultra 8.0 software, then energetically minimized by using MOPAC with 100 iterations and minimum RMS gradient of 0.10. The AutoDock Tool (ADT) automatically computes Gasteiger charges to the 3D structures of the ligands.…”

Section: Molecular Docking Studymentioning

confidence: 99%

“…Compared to other COX/ 5-LOX inhibitors which showed also good GIT tolerance, licofelone is the only COX/5-LOX inhibitor that showed an acceptable safety level in clinical use [17]. The replacement of the 4-chlorophenyl group at C5 in licofelone with a 5-chlorothiophen-2-yl moiety in compound 3 resulted in almost the same COX-1/5-LOX inhibitory activity [18]. In order to avoid the gastric side effects, several reported pyrrolizines with nonselective COX inhibitory activity lacking the distinctive free carboxylic group were designed [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, and Biological Evaluation of Some Novel Pyrrolizine Derivatives as COX Inhibitors with Anti-Inflammatory/Analgesic Activities and Low Ulcerogenic Liability

et al. 2016

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Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed anti-inflammatory and pain relief medications. However, their use is associated with many drawbacks, including mainly serious gastric and renal complications. In an attempt to circumvent these risks, a set of N-(4-bromophenyl)-7-cyano-6-substituted-H-pyrrolizine-5-carboxamide derivatives were designed, synthesized and evaluated as dual COX/5-LOX inhibitors. The structural elucidation, in vivo anti-inflammatory and analgesic activities using a carrageenan-induced rat paw edema model and hot plate assay, were performed, respectively. From the results obtained, it was found that the newly synthesized pyrrolizines exhibited IC 50 values in the range of 2.45-5.69 µM and 0.85-3.44 µM for COX-1 and COX-2, respectively. Interestingly, compounds 12, 13, 16 and 17 showed higher anti-inflammatory and analgesic activities compared to ibuprofen. Among these derivatives, compounds 16 and 19 displayed better safety profile than ibuprofen in acute ulcerogenicity and histopathological studies. Furthermore, the docking studies revealed that compound 17 fits nicely into COX-1 and COX-2 binding sites with the highest binding affinity, while compound 16 exerted the highest binding affinity for 5-LOX. In light of these findings, these novel pyrrolizine-5-carboxamide derivatives represent a promising scaffold for further development into potential dual COX/5-LOX inhibitors with safer gastric profile.

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Spectrofluorimetric Quantification of Malondialdehyde for Evaluation of Cyclooxygenase-1/Thromboxane Synthase Inhibition

Dannhardt

Flemmer

Hartmann

et al. 1998

Arch. Pharm. Pharm. Med. Chem.

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The in vitro assay developed by Hartmann and Ledergerber (1995)[1] utilizing the Spectrofluorimetric quantification of malondialdehyde after reaction with thiobarbituric acid was modified and used for further investigations. The human whole blood was replaced by a platelet suspension of pig blood, and calcium ionophore A23187 was used instead of collagen for inducing the arachidonic acid cascade. The modified assay represents a simple, time and cost saving method for the evaluation of cyclooxygenase‐1/thromboxane synthase inhibition. The reproducibility and comparability of results is given. Additional experiments allow classification of selective phospholipase A2, cyclooxygenase‐1, and thromboxane synthase inhibitors. Further studies of malondialdehyde formation show that the cyclooxygenase and/or the thromboxane synthase are competitively inhibited by reaction products of the cyclooxygenase pathway by a negative feedback mechanism.

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Synthesis and Evaluation of a Novel Series of Pyrrolizine Derivatives as Dual Cyclooxygenase‐1 and 5‐Lipoxygenase Inhibitors

Cited by 26 publications

References 25 publications

Reactivity of 2‐substituted imidazo[1,2‐b]pyridazines: Preparation of 3‐nitro, nitroso and chloro derivatives

Reactivity of 2‐substituted imidazo[1,2‐b]pyridazines: Preparation of 3‐nitro, nitroso and chloro derivatives

Design, Synthesis, and Biological Evaluation of Some Novel Pyrrolizine Derivatives as COX Inhibitors with Anti-Inflammatory/Analgesic Activities and Low Ulcerogenic Liability

Spectrofluorimetric Quantification of Malondialdehyde for Evaluation of Cyclooxygenase-1/Thromboxane Synthase Inhibition

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