Computational Modeling Studies Of Novel Triazinone H-DAAO Inhibitors And Synthesis Of N-ethyl Dabigatran Derivatives

Human D-amino acid oxidase?h-DAAO?can effectively act on D-serine,which has been actively explored as a novel therapeutic target for treating schizophrenia.Dabigatran is an anticoagulant drug used for the treatment of cardiovascular diseases,but there are some deficiencies,so its structural modification and synthesis studies are necessary.In the first part of this paper,the systematic theoretical research on h-DAAO inhibitors was performed by using 3D-QSAR,molecular docking,molecular dynamics and ADME prediction.Firstly,37 triazinone derivatives as h-DAAO inhibitors were obtained to construct the 3D-QSAR model,indicating that the model has good predictability and strong stability.Based on the structure-activity relationship studies,a total of nine new h-DAAO inhibitors were designed,which exhibited good predicted activities.Four essential residues?i.e.,Gly313,Arg283,Tyr224 and Tyr228?were considered to interact with the inhibitor through molecular docking.The hydrogen bond produced by the triazine structure with protein and the hydrophobic interaction with the residues?i.e.,Leu51,His217,Gln53 and Leu215?inproved the stability of the inhibitor at the binding site of protein.Additionally,the compounds D1,D3and D8 with higher predictive activities and good docking scores,were selected as representative inhibitors for dynamics simulation and ADME prediction.It confirms that the newly designed candidate compounds have in-depth research value.In the second part of this paper,three aromatic ring substituted dabigatran derivatives were designed according to the analysis of the structure-activity relationship.Then they were synthesized by Michael,acylation,reduction,condensation ring-closing,Pinner and hydrolysis reactions.Furthermore,structures of new synthesized compounds were confirmed by ¹H NMR,¹³C NMR and HR-MS.Finally,melting point test were done.Compounds 9a⁹c can be used as a potential anticoagulant candidate compound for further research.This paper could offer a reliable theoretical basis for future structural optimisation,design and synthesis of effective antipsychotics.And it has great reference significance for the in-depth study of novel dabigatran derivatives.