Design, Synthesis and Anti-inflammatory Activity of Derivatives 10-R-3-Aryl-6,7-dihydro-2H-[1,2,4] triazino[2,3-c]quinazolin-2-ones of Spiro-fused Cyclic Frameworks

Abstract

Present work is devoted to the purposeful search of novel promising anti-inflammatory agents among the insufficiently known 3'-R-10'-R 1 -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.

Tandem heterocyclization of 2‐(azolyl‐(azinyl‐))anilines as an efficient method for preparation of substituted pyrrolo[1,2‐a]azolo‐(azino‐)[c]quinazolines

“…In the same time, the reaction of compounds 1‐3 with ethyl chloroformate, N , N ′‐carbonyldiimidazol, carbon disulfide, and sodium (potassium) O‐methyl carbonodithioates yielded dihydroazolo‐(azino‐)[ c ]quinazoline‐ones(thiones) . The usage of carbonyl‐containing compounds and their synthetic equivalents (aldehydes, ketones, paraform, acetals, and aldehydo acids) as electrophiles allowed to obtain partially hydrogenated or spiro‐condensed analogues . Similar results, namely, formation of 6,7‐dihydro‐2 H ‐[1,2,4]triazino[2,3‐ c ]quinazolines, were observed in the reaction of substituted 3‐(2‐aminophenyl)‐6‐ R ‐1,2,4‐triazin‐5(2 H )‐ones with DMAD, whereas reaction of 3‐(2‐aminophenyl)‐6‐ R ‐1,2,4‐triazin‐5(2 H )‐ones with о‐formylbenzoic and opianic acid occurred as tandem formation of pyrimidine and isoindole fragments that yielded corresponding isoindolo[2,1‐ a ][1,2,4]triazino[2,3‐ c ]quinazolines .…”

“…Considering the originality of mentioned reaction, the study of 2‐(azolyl‐(azinyl‐))anilines reactivity relative to such electrophiles as 4‐ R ‐4‐oxocarboxylic acids is quite interesting. Moreover, obtained polycyclic products are promising as bioactive agents with anticancer, antibacterial, antiviral, hypoglycemic, hypolipidemic, anticonvulsant, etc activities …”

Synthesis, Molecular Docking and Biological Properties of Novel Thiazolo[4,5-b]pyridine Derivatives

“…It was found out that for N 3 -substituted 5-hydroxy-7-methyl-3H-thiazolo [4,5b]pyridin-2-one derivative (4), obtained via [3+3]cyclocondensation 3-phenyl-4-iminothiazolidone-2-onе with ethyl acetoacetate, the presence of phenyl goup in the N 3 position contributed to the inflammation inhibition efficiency. The presence of cyano and carboxy groups substituents (5,6) in the core scaffold N 3 position lead to the high anti-inflammatory activity even exceeding the Ibuprofen…”

“…4 These conditions generate one of the biggest challenges of modern medicinal chemistry for the development of alternative anti-inflammatory drugs with minimal adverse effects. [5][6][7] No less challenging is the search for new antioxidants. Different environmental stress factors like pollution, drought, temperature, excessive light intensities, and nutritional limitation can increase the production of reactive oxygen species (ROS).…”

Directed Search of Biologically Active Compounds among Hydrogenated Isoindolylalkyl(alkylaryl-,aryl-)carboxylic Acids with Quinazoline Fragment that Modify the Carbohydrate Metabolism: Design, Synthesis and Modification

“…Quinazoline derivatives and their condensed analogues have always attracted the attention of medicinal chemists as objects of advanced research, aimed at the elaboration of new drugs. This fact is explained by the high biological activity of natural, [1][2][3] as well as synthetic quinazolines [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] and, undoubtedly, their wide ability to chemical modification. [10][11][12][13]18 In recent years, the interest for this heterocyclic system has increased greatly since the introduction of in silico approaches to the drug search strategy, combinatorial chemistry and high-throughput screening.…”