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Synthesis and Biological Activity of A Novel Non-steroidal Anti-inflammatory Drug ML4000

Author: ZhengZhiChao
Tutor: SunYouGuang
School: Tianjin University of Technology
Course: Medicinal Chemistry
Keywords: NSAIDs Licofelone NO donor Synthesis Biological activity
CLC: R96
Type: Master's thesis
Year: 2011
Downloads: 34
Quote: 0
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Abstract


Objective: To synthesize the nitric-oxide-releasing nonsteroidal anti-inflammatory drugs （NO-NSAIDs） ML4000 with a cyclooxygenase （COX） and 5-lipoxygenase （5-LOX） dual inhibitor licofelone （ML3000）, and evaluate its biological activity. Methods: ML4000 was synthesized through nine steps.2-Benzyl-4,4-dimethyl-1-pyrroline was prepared with 3,3-dimethyl propanediol as the starting material via condensation, ring-opening and substitution reaction, and then after addition reaction with benzylmagnesium chloridethe and ring-forming reaction withα-bromo-4-chloroacetophenone the key intermediate substituted pyrrolizinone was obtained. ML3000 was synthesized from the pyrrolizinone by the Friedel-Crafts reaction with oxalyl chloride and Huangminglong reaction sequentially. The target product of ML4000 was finally obtained from the sodium salt of ML3000, 1,4-dibromobutane and AgNO3 through condensation. Biological activity tests included the preliminary in-vivo metabolism of ML4000 （po）, evaluation of anti-in?ammatory activity using the xylene-induced mice ear edema model and carrageenan-induced rat paw oedema model, observation of gastric mucosal surface bleeding and ulcers, and fecal occult blood after continuous oral administration, and determination of NO release from ML4000 （po）.Results: ML4000 was synthesized with a yield of 11% and confirmed by IR, MS,1H NMR, 13C NMR and elemental analysis. In rats,the metabolite ML3000 of ML4000 (10mg·kg-1, po) was detected after 0.25h;it was found to be equipotent to ML3000 in anti-inflammatory activity;no gastrointestinal bleeding and ulcers was found in rats at 60mg·kg-1 po for consecutive 14 days,significant increase of NO on the serum and gastric mucosa after 1 h at 60mg·kg-1 po。Conclusion: The ML4000 chemical structure consists of one ML3000 molecule covalently bound to one NO-donating moiety, butanediol mononitrate. In vivo, the ML4000 molecule is metabolized to the NSAID, ML3000, and NO. The preliminary bioassay showed that it has good anti-inflammatory activity and gastrointestinal tolerability and significant NO releasing activity。

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