Abstract
Present work is devoted to the purposeful search of novel promising anti-inflammatory agents among the insufficiently known 3'-R-10'-R1-spiro[hetaryl-3(4),6'-[1,2,4]triazino[2,3-c]quinazolin]-2'(7'H)-ones. The virtual combinatorial library of previously unknown spiro-condensed derivatives of [1,2,4]triazino[2,3-c]quinazolines was formed and promising COX-2 inhibitors were identified by molecular docking method. Potential anti-inflammatory agents were synthesized by [5+1]-cyclocondensation of substituted 3-(2-aminophenyl)-6-R-1,2,4-triazin-5(2H)-ones with heterocyclic ketones. The structures of synthsized compounds were verified by complex of physicochemical methods and spectral characteristics features were discussed. Obtained compounds were studied for anti-inflammatory activity using formalin induced paw edema model and highly active compounds were identified. Conducted SAR-analysis showed that combination of triazino[2,3-c] quinazoline moiety with spiro-condensed fragments is a reasonable approach for creating novel anti-inflammatory agents.
Highlights
Inflammation is a chain of complex metabolic and morphological changes, aimed to restore the functions of the damaged tissues or organ in general
Considering the roles of cyclooxygenases (COX-1 and COX-2) as important pharmacological targets and their inhibitors are the basis for the developing of anti-inflammatory drugs, in the first phase of the study the virtual base (80 compounds) of 3’-R-10’-R1-spiro [hetaryl-3(4),6’-[1,2,4]triazino[2,3-c]quinazolin]-2’(7’H)ones was analyzed using molecular docking
Complexes of COX-1 and COX-2 were downloaded from the Protein Data Bank, to determine the affinity (Table 1), http://www.rcsb.org/pdb/home/home. do
Summary
Inflammation is a chain of complex metabolic and morphological changes, aimed to restore the functions of the damaged tissues or organ in general. The use of drugs such as NSAIDs, may correct as certain stages of inflammation, so exclude the process in general. The majority of studies focus on substances with a heterocyclic fragment.1 This signifies considerable side effects of NSAIDs of first generation (COX-1), namely their negative impact on the gastrointestinal tract (gastrotoxicity). The mentioned strategy with the use of de novo methodology (molecular docking) and X-ray analysis of the macromolecules active-site has significantly changed the direction of the synthetic work aimed at creating the drugs for correcting the inflammation. That is based on rational design, namely structural similarity to a number of innovative and well-known drugs and forecasting the likely biological effects (COX inhibitors) using methods of computer modeling and in vivo tests
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