Demetrios N. Nicolaides

Natural and Synthetic Coumarin Derivatives with Anti-Inflammatory / Antioxidant Activities

Several natural products with a coumarinic moiety have been reported to have multiple biological activities. It is to be expected that, in a similar way to isomeric flavonoids, coumarins might affect the formation and scavenging of reactive oxygen species (ROS) and influence processes involving free radical-mediated injury. Coumarin can reduce tissue edema and inflammation. Moreover coumarin and its 7-hydroxy-derivative inhibit prostaglandin biosynthesis, which involves fatty acid hydroperoxy intermediates. Natural products like esculetin, fraxetin, daphnetin and other related coumarin derivatives are recognised as inhibitors not only of the lipoxygenase and cycloxygenase enzymic systems, but also of the neutrophil-dependent superoxide anion generation. Due to the unquestionable importance of coumarin derivatives considerable efforts have been made by several investigators, to prepare new compounds bearing single substituents, or more complicated systems, including heterocyclic rings mainly at 3-, 4- and/or 7-positions. In this review we shall deal with naturally occurring or synthetically derived coumarin derivatives, which possess anti-inflammatory as well as antioxidant activities.

Synthesis and biological evaluation of several coumarin-4-carboxamidoxime and 3-(coumarin-4-yl)-1,2,4-oxadiazole derivatives

A series of novel coumarin-4-carboxamidoximes 6a-g and 3-(coumarin-4-yl)-1,2,4-oxadiazoles 9a-e were synthesized from coumarin-4-carboxaldehyde 1 via the intermediate coumarin-4-nitriloxide 4. These coumarin derivatives were isolated and characterized, and evaluated for their ability to inhibit trypsin, glucuronidase, and soybean lipoxygenase. The compounds were also tested for antioxidant activity, and as antiiflammatory agents in the rat carrageenin paw edema assay.

Recent Developments in the Chemistry and in the Biological Applications of Amidoximes

Amidoximes are compounds bearing both a hydroxyimino and an amino group at the same carbon atom which makes them versatile building blocks for the synthesis of various heterocycles. Their importance in chemistry along with their rich biology, make amidoximes an attractive target for medicinal chemists, biochemists and biologists. Amidoximes and simple O-substituted derivatives possess very important biological activities functioning as antituberculotic, antibacterial, bacteriostatic, insecticidal, elminthicidal, antiviral, herbicidal, fungicidal, antineoplastic, antiarrythmic, antihypertensive, antihistaminic, anxiolytic-antidepressant, anti-inflammatory/antioxidant, antiaggregatory (NO donors) or plant growth regulatory agents. A number of amidoximes has already been used as drugs, or currently being in clinical trials. Their numerous pharmaceutical applications have been recently enriched, due to the fact that some mechanistic pathways, concerning their conversion to amidines, as well as their ability to release NO were clarified, giving a new insight to their mode of action and allowing the design of new therapeutic agents. The main subject of the present review paper is to highlight aspects concerning chemical and biological questions on this interesting class of compounds. Some new synthetic methodologies as well as improvements of previously reported general reactions involving amidoximes, acylated amidoximes, and amidines are presented. The biological applications of amidoximes over the end of 2006 are also extensively reviewed.

Reactions of furoxans with phosphorus ylides

Abstract Benzofuroxan ( 1 ) reacts with phosphorus ylide 2 to give benzimidazole derivatives 8 and 10 , Whereas reaction of 1 with ylide 12 furnishes quinoxaline 17 via an Initial Wittig-type reaction. Similarly the reaction between the furoxano[3.4-b]quinoxalines 19a or 19b and the ylide 2 yielded compounds 22a and 22b , respectively. In these reactions as well as in the reactions of the above furoxans with other phosphorus ylides, a significant deoxygenation of the furoxans to furazans with subsequent oxidation of the ylides is generally observed.

1-8H-pyrano[3,2-g]benzoxazol-8-ones from 7-methoxyimino-4-methylchromene-2,8-dione

Abstract 7-Methoxyimino-4-methylchromene-2,8-dione 3, easily prepared from the quinone 1 reacts thermally with methylaromatics 5(a–g), benzyl derivatives 13(a–c), halo derivatives 14(a–c) to give mainly oxazolocoumarins. Products 8(a–d) are obtained from 5(a–d), 13(a–c). Compound 9 is obtained from 5(a–c) and 13(a–c), compounds 15(a–c) are obtained from 14(a–c), the aminophenol 10 and coumarin 16 are obtained from 5f and 14c respectively, while coumarin 12 is obtained from 5g. The reaction of 3 with N-methyl-aniline and N,N-dimethylbenzylamine gives compound 10 and 8a respectively.

Synthesis and biological evaluation of novel angular fused Pyrrolocoumarins.

Angular pyrrolocoumarins were synthesized from the reaction of 4-hydroxyindole or 5-hydroxyindole with DMAD and PPh3 and were tested for anti-inflammatory and antioxidant activity. These compounds significantly inhibited the carrageenin-induced paw edema (60.5%–73.4%) and have important scavenging activity. Although their interaction with the free stable radical DPPH is not high, compound 9 is the most potent (73.4%) in the in vivo experiment. Compound 7 seems to be a potent LOX inhibitor. An attempt was made to correlate the biological results with their structural characteristics and physicochemical parameters.

Reactions of 2-(methoxyimino)benzen-1-ones with α-alkylethoxycarbonylmethylene(triphenyl)phosphoranes

Abstract The title 2-(methoxyimino)benzen-1-ones react with α-alkylethoxycarbonylmethylene(triphenyl)phosphoranes to give 2 H -[ b ][1,4]benzoxazine derivatives along with benzoxazole and indole derivatives. Reaction mechanisms to explain the formation of products obtained are suggested.

Synthesis of phenanthro[9, 10-d]oxazoles from 10-(methoxyimino)phenanthrene-9-one

Abstract 10-(Methoxyimino)phenanthren-9-one 3 easily reacts with the methyl substituted aromatics 4(a–d), as well as with α-bromo-p-xylene 6 and the α-substituted methyl derivatives 7(a–i), to afford in 5–64% yield the corresponding 2-aryl substituted phenanthro[9, 10-d]oxazoles 5(a–g), most probably via a free radical reaction sequence. In several cases the unsubstituted oxazole 12 is also obtained, while reaction of compound 3 with the N-methyl substituted amines 7g and 14(a,b) leads to the aminooxazoles 13 and 15(a,b) respectively.

Synthesis of 1-methoxy-1H-phenanthro[9,10-c][1,2]oxazine and its transformation to triphenylene-o-dicarboxylic derivatives

Abstract 1-Methoxy-1H-phenanthro[9,10-c][1,2]oxazine 4 prepared from teh reaction of 10-(methoxyimino)phenanthren-9-one 1 with benzoylmethylene(triphenyl)phosphorane 2, reacts thermally with dienophiles 6, 9a, b to give the triphenylene-o-dicarboxylic derivatives 8, 11a,b in high yield.

Reactions of 4-methylchromene-2,7,8-trione with phosphonium ylides. Synthesis and evaluation of fused 1,3-dioxolocoumarins as antioxidants and antiinflammatories

4-Methylchromene-2,7,8-trione 1 reacts with stabilized 2a–c and non-stabilized ylides 11a–c bearing an α-methylene group to give 7,8-fused 1,3-dioxolocoumarins 4a–c and 12a–c along with betaine 6 and 7-hydroxycoumarin derivative 9. The reaction of 4,5-fused 1,3-dioxolo-o-benzoquinone 13 with the ylide 14 leads to 4-ethoxycarbonylayapin 18 and benzofuranone 19. Deethoxycarbonylation of 18 gives ayapin 20. Compounds 4b, 12a–c, 18 and 20 were tested for their ability to interact with 1,1-diphenyl-2-picrylhydrazyl stable free radical (DPPH), to scavenge superoxide anion radicals, to compete with DMSO for hydroxyl radicals, and to inhibit proteolysis, β-glucuronidase and soybean lipoxygenase activity in vitro. These compounds were also tested for their effect on the ferrous ion-stimulated peroxidation of linoleic acid. They showed a potent inhibitory effect (55–57%) against inflammation induced by carrageenan in the rat paw edema model. On the contrary their reducing ability was found to be low and no inhibition on soybean lipoxygenase was recorded.