Study On Synthesis And Anti-inflammatory Activity Of Flavone Derivatives

Nonsteroidal anti-inflammatory drug（NSAIDs） are widely used in many countries.They were not only used in the treatment of rheumatoid arthritis,osteoarthritis,other arthritis,some diseases associated with arthritis and pain,but also used in the preservation of colon cancer and Alzhemimer’s disease（AD） etc.However,most of NSAIDs used in clinic now tend to induce gastrointestinal damage,nephrotoxicity and hepatotoxicity.Therefore,the discovery of novel anti-inflammatory with higher effects and lower toxicities has been an important research field.Flavonoids are a family of naturally compounds that are abundant in plant kingdom.These natural compounds as potential therapeutic agents have been of interest to the medicinal chemists for many years because of their broad biological activities such as antitumour,antioxidant, antiallergic and anti-inflammatory etc.Most of the flavonoids were isolated from plants,however, they were generally unsuitable for medicinal development for the reason of restricted chemical-physical properties and limited sources etc.Meanwhile,the structure-activity studies and the pharmacological mechanism of the actions of these compounds have not been adequately evaluated due to the limited quantities of flavonoids.So the synthetic study has got more and more attention.The general strategies for chemical modification of flavonoids are two respects:one is the chemical modification of natural flavonoids,the other is the chemical modification of basic nucleus.In order to discover novel synthetic flavones with potent anti-inflammatory,60 flavone derivatives modified on the A and B rings of basic nucleus were synthesized.The structures of these compounds were characterized with MS,IR,¹H NMR,in which 48 compounds are not reported in the literature based on search by SciFinder.The anti-inflammatory activities of some target compounds were evaluated using the croton oil-induced ear edema test in mice.According to screening results, 4’-methoxy-7-[2-（4-morpholinyl）-2-oxoethoxy]flavone（23）, 4’-chloro-7-（2-dimethylamino-2-oxoethoxy）（29）,2-phenyl-9-（4-methoxylphenyl）-9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-one（38）, 2-phenyl-9-benzyl-9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]oxazin-4-one（41）, 8-phenyl-2-（4-methoxylphenyl）-2,3-dihydro- 1H,10H-chromeno[5,6-e][1,3]oxazin-10-one（46） and 2-phenyl-8-（4-flurobenzoyl）-9-methylfuro[2,3-h]chromene（60） showed some anti-inflammatory activity at a dose of 200mg/kg.6-[2-（4-morpholinyl）ethoxy]flavone（1）,6-[2-（1-piperidinyl）ethoxy] flavone（5）,8-phenyl-2-benzyl-2,3-dihydro-1H,10H-chromeno[5,6-e][1,3]oxazin-10-one（51） and 2-Phenyl-8-（4-nitrobenzoyl）-9-methylfuro[2,3-h]chromene（55） showed significant anti-inflammatory activity at a dose of 200mg/kg.Some 3D-SAR of these compounds was discussed in this dissertation.The calculations of comparative molecular field analysis（CoMFA） and comparative molecular similarity indices analysis were carried out on an SGI IRIX workstation with Tripos’ Sybyl.The results imply that the enhancement of steric effect on B-ring and C₅ and C₆ on A-ring is beneficial to the improvement of anti-inflammatory activities.