The Design And Synthesis Of The Inos Inhibitor And Inos Inhibition Activity Was Measured

The endogenous synthesis of nitric oxide is derived from the oxidation of the terminal guanidyl of L-arginine, mediated by a family of enzymes known as nitric oxide synthase(NOS), which have been classified as constitutive(cNOS) and inducible (iNOS) isoforms. The excess production of NO caused by iNOS has been implicated in numerous disease states, inhibition of iNOS activity by its inhibitors, therefore, being of significant therapeutic benefit.Most of the iNOS inhibitors reported in the literature have guanidyl as a functional group. Base on this key factor, complex(I), biguanidine and its derivatives(IIa-IIh), triazines(IIIa-IIIh), which all have two guanidyls, were designed and synthesized.Complex(I) was readily prepared by the reaction of cupric sulphate with dicyandiamide, the structure of which was characterized by EA, Atomic Absorption, 'H-NMR, IR and UV. Biguanide hydrochloride was prepared by the reaction of dicyandiamide and ammonia water, cupric chloride as a catalyst. Alkylbiguanide sulphates(IIb-IIh) were prepared by the nucleophilic addition reaction of alkylamines with complex(I). For Ilb-IIg, after the synthesis of complex(I), alkylamines were added directly into the reaction mixture, while for IIh , complex(I) was isolated and the following reaction was carried out in the 95% ethanol because of the poor solubility of n-octylamine in water. In addition, the preparation conditions of butylbiguanide sulphate(IIe) were studied by orthogonal test. Triazines(IIIa-IIIh) were synthesized by "two-component synthesis" method, namely, by the reaction of alkylbiguanide sulphates and carbonyl compounds in the presence of H2SO4 as a catalyst. Continuous removal of water from the reaction system and careful control of acid concentration were found to be critical factors. In the reaction, triethyl orthoformate was used as a water scavenger and the PH value was controlled in the range of 5-6. The structure of biguanidine and its derivatives (Ila-IIh) , triazines (Illa-IIIh) were characterized by 'H-NMR, IR and UV.The iNOS inhibitory activity assays were conducted for complex (I) , Ila-IIh and Illa-IIIh in vitro. The results showed that compound complex (I), Ila and IId possessed iNOS inhibitory activity, complex (I) showing superior activity to the control compound aminobiguanidine, Illa-IIIh, however, showing no iNOS inhibitoryactivity.