ABSTRACT
An environmentally friendly oxidation system has proposed for the practical and scalable production of value-added 2,5-furandicarboxylic acid from 1â kg of 5-hydroxymethylfurfural. The system is composed of a simple base, oxygen, and a green solvent, thereby providing a sustainable and economical approach to organic synthesis. To gain insight into the mechanism of this oxidation process, NMR spectroscopic analysis and kinetic study are used for the mechanistic investigation of this environmentally friendly oxidation process.
ABSTRACT
We describe the synthesis and biological evaluation of N-aryl-5-aryloxazol-2-amine derivatives that are able to inhibit 5-lipoxygenase (5-LOX), a key enzyme of leukotriene synthesis, for the treatment of inflammation-related diseases including asthma and rheumatoid arthritis. A novel structural moiety containing oxazole was initially identified from a chemical library using an in vitro enzymatic and cell-based assay, and its synthesized oxazole derivatives were further examined to develop a structure-activity relationship (SAR). SAR analysis demonstrated that a hydroxyl or amino group at the p-position on N-phenyl was essential for the 5-LOX-inhibitory activities of the derivatives, and that other halogen and methyl group-substituted derivatives affected the potency, positively or negatively. As a result, derivatives selected through first-round screening were further optimized using a cell-based assay and an in vivo assay to develop a potent, selective 5-LOX inhibitor. A final hit exhibited an improved efficacy in arachidonic acid-induced ear edema when applied topically but not orally. Moreover, it showed the additional advantage of sustainable antiinflammatory activity over a reference compound, zileuton. Taken together, chemical entities bearing an oxazole scaffold could be promising as therapeutic drugs for the treatment of chronic inflammatory skin disorders.
Subject(s)
Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Arachidonate 5-Lipoxygenase/metabolism , Lipoxygenase Inhibitors/chemistry , Lipoxygenase Inhibitors/therapeutic use , Oxazoles/chemistry , Oxazoles/therapeutic use , Amines/chemical synthesis , Amines/chemistry , Amines/pharmacology , Amines/therapeutic use , Animals , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Arachidonic Acid , Cell Line , Ear/pathology , Edema/chemically induced , Edema/drug therapy , Edema/enzymology , Edema/pathology , Humans , Inflammation/chemically induced , Inflammation/drug therapy , Inflammation/enzymology , Inflammation/pathology , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/pharmacology , Mice , Oxazoles/chemical synthesis , Oxazoles/pharmacology , Structure-Activity RelationshipABSTRACT
Biological evaluation of N-aryl-4-aryl-1,3-thiazole-2-amine derivatives was examined for anti-inflammatory activity in in vitro and in vivo assays. The thiazole compounds showed direct inhibition of 5-lipoxygenase (LOX) that is a key enzyme of leukotrienes synthesis and involved in the inflammation-related diseases, including asthma and rheumatoid arthritis. To optimize biological activity, we synthesized 1,3-thiazole-2-amine derivatives and investigated for structure and activity relationship. Especially, N-(3,5-dimethylphenyl)-4-(4-chlorophenyl)-1,3-thiazole-2-amine was shown to have a potent anti-inflammatory activity as a 5-LOX inhibitor.
Subject(s)
Amines/chemistry , Anti-Inflammatory Agents/chemical synthesis , Arachidonate 5-Lipoxygenase/chemistry , Lipoxygenase Inhibitors/chemical synthesis , Thiazoles/chemistry , Administration, Oral , Amines/pharmacology , Amines/therapeutic use , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Arachidonate 5-Lipoxygenase/metabolism , Cell Line, Tumor , Edema/drug therapy , Lipoxygenase Inhibitors/pharmacology , Lipoxygenase Inhibitors/therapeutic use , Mice , Rats , Structure-Activity RelationshipABSTRACT
A series of 3-substituted-benzofuran-2-carboxylic esters was synthesized and evaluated for biological activity as ischemic cell death inhibitors in H9c2 cells and rat primary cardiac myocytes under conditions of oxygen and glucose deprivation. The introduction of a sulfur atom at the three-position substituent of the benzofuran ring markedly improved ischemic cell death inhibitory potency. In particular, 3-[2-(4-nitro-phenylsulfanyl)-acetylamino]-benzofuran-2-carboxylic acid ester (10) (EC(50)=0.532 µM, cell death=6.18%) and 4-chloro-3-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzofuran-2-carboxylic ester (18) (EC(50)=0.557 µM, cell death=7.02%) were shown to be the most potent in this series of benzofuran analogs.
Subject(s)
Benzofurans/chemical synthesis , Benzofurans/pharmacology , Cell Death/drug effects , Myocardial Ischemia/pathology , Animals , Carboxylic Acids/chemistry , Cell Line , Esters/chemistry , RatsABSTRACT
[reaction: see text] The resolution in the lithiation-substitution sequence from 1 to 4-11 in MTBE is shown to be under thermodynamic control in contrast to the previous report of kinetic control in diethyl ether. Diastereomeric equilibration of a soluble complex is shown to be controlling and an asymmetric synthesis of a 3,4,5-substituted benzazepine is reported.
Subject(s)
Benzazepines/chemical synthesis , Catalysis , Lithium/chemistry , Molecular Structure , Solvents , ThermodynamicsABSTRACT
[reaction: see text] A number of highly substituted indenes have been prepared in good yields by treating functionally substituted aryl halides with various internal alkynes in the presence of a palladium catalyst. The reaction is believed to proceed by regioselective arylpalladation of the alkyne and subsequent nucleophilic displacement of the palladium in the resulting vinylpalladium intermediate.
