Abstract:

The ability scavenging nitric oxide makes nitronyl nitroxides to be promising dr ugs for the treatments of various diseases caused by excess production of NO. Id entifying the preferential structure for the NO scavenger in the present paper the 2-alkyl, 2-heterocycle and 2-substitutedphenylnitronyl nitroxides were syn thesized and their in vitro NO scavenging activities were assayed. In the presen ce of Br 2 and NaOH 2-nitropropane was smoothly converted into di-tert-butyl bishydroxylamine (1) in 40% total yield. The condensatio n of 1 and corresponding a ldehydes provided the corresponding 2-substituted-1,3-dihydroxy-4,4,5,5-tet ramethylimidazolindine 2a-h in 5 3%, 69%, 83%, 73%, 69%, 85%, 51%, and 63% yield, respectively. With PbO 2 as oxidation agent 2a-h were converted into the cor responding nitronyl nitroxides 3a-h in 99%, 38%, 88%, 83%, 79%, 80%, 52% and 7 3% yield, respectively. In the ESR measurements 3a-h gave typical NO spectra, d emonstrating they were chemically stable free radicals. In the aortic strip expe riments 3a-h dose-dependently an d 2-substituent-dependently inhibited Ach-i nduced vasorelaxation. 100 μmol/L and 10 μmol/L of 3a-h exhibited obvious NO scavenging activity(compare to vehicle, P<0.001). At the concentration of 1 μmol/L however only 4-hydroxyphenylnitronyl nitroxide (3g) exhibited obvious NO scavenging effect (compare to ve hicle, P<0.001). The activities of the hig h dose were higher than that of moderate dose (P<0.001) and the activities o f the moderate dose were higher than that of low dose (P< 0.001). Based on the observations it is concluded that nitronyl nitroxides are useful NO scavenger and 2-substitutednitronyl nitroxide may be selected as the desirable lead compo und in the development of NO scavenger.Based on the observations that 2-substit utedphenylnitronyl nitroxides were chemically most stable and bioactive it is co ncluded that nitronyl nitroxides are useful NO scavenger and 2-substitutedpheny lnitronyl nitroxide may be selected as the desirable lead compound in the development of NO scavenger.