Synthesis Of The New Bromophenols With Nitrogen-containing Heterocycle And Their Inhibitory Activities Against The H₂O₂ Induced Injury In Endothelial-derived EA.hy926 Cells

Objective:As a natural active compound from marine red algae, the halophenols have became a important valuable lead compound because of its variety biological activities and multiple molecular skeleton structures. In this paper, we took a bromophenol compound-5,2’-dibromo-2,4’,5’-trihydroxydiphenylmethanone(LM49)- as a lead compound and made a structural modification. A series of new nitrogen-containing bromopenols were obtained, compounds with better biological activities and new structures were expected to be found among them.Methods:(1) We took 5-bromo-2-methy-benzoic acid as a starting material, by Friedel-Crafts acylation, bromine substitution reaction, radical substituted reaction, nitrogen-containing heterocyclic nucleophilic substituted reaction, and demethylation reaction, and then new nitrogen-containing heterocyclic bromophenols can be obtained;(2) All the target compounds and their corresponding intermediate compounds were evaluated for their in vitro inhibitory activities against the H2O2-induced injury in endothelial-derived EA.hy926 cells.Results:(1) 36 nitrogen-containing heterocyclic diphenylmethanones bromophenols and 36 intermediate compounds were designed and synthesized, their structures were confirmedby ESI-MS,1H NMR, and13 C NMR spectrum, some of the bromophrnols were confirmed by HRMS, and all of them have not been reported in the literature;(2) 13 target compounds and 15 intermediate compounds had significant protective activities. The EC50 value of W22 a, a target compound of piperazine bromophenols, was 0.9 μM, which was comparable to the lead compound LM49(the EC50 value was 0.7μM).Conclusions:(1) 36 nitrogen-containing heterocyclic diphenylmethanones bromophenols and 36 intermediate compounds were obtained, all of them have not been reported in the literature,and a new synthetic route was established;(2) 13 target compounds and 15 intermediate compounds were found had significant inhibitory activities against the H2O2 induced injury in endothelial-derived EA.hy926 cells by preliminary in vitro activity screening. The EC50 value of W22 a, a target compound of piperazine bromophenols, was 0.9 μM, which was comparable to the lead compound LM49.