RESUMEN
BACKGROUND: Computer-aided drug design is among the most effective methods of medicinal chemistry. The above mentioned approach is used for the purposeful search of antiinflammatory agents among quinazoline condensed derivatives. OBJECTIVE: The study aimed to conduct a purposeful synthesis of novel 3-R-2,8-dioxo-7,8-dihydro- 2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline-5a(6H)carboxylic acids and their salts as promising anti-inflammatory agents, evaluate their structure by physicochemical methods and establish their anti-inflammatory activity. METHODS: The structures of target compounds were proposed due to their structure similarity to existing drugs and experimental agents with anti-inflammatory activities. The features of the synthesized compounds structures were evaluated by IR-, NMR spectroscopy and chromatography-mass spectrometry and discussed in detail. Probable molecular mechanisms of activity were predicted by molecular docking. The anti-inflammatory activity was determined by their ability to reduce the formalin- and carrageenan-induced paw edema in rats. RESULTS: It was found that the condensation of 3-(2-aminophenyl)-6-R-1,2,4-triazin-5(2H)ones with 2-oxoglutaric acid yielded 3-R-2,8-dioxo-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline- 5a(6H)carboxylic acids which may be considered as a promising anti-inflammatory agent. An in silico study showed that the obtained compounds revealed affinity to the molecular targets and corresponded to the drug-like criteria. Additionally docking study allowed to estimate the nature of interactions between synthesized compounds and molecular targets. The in vivo experiments showed that the obtained compounds demonstrated significant anti-inflammatory activity comparable or higher than the activity of the reference drug Diclofenac. CONCLUSION: The developed and implemented search strategy of the anti-inflammatory agents was justified. 3-R-2,8-dioxo-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline5a(6H)carboxylic acids possessed the anti-inflammatory activity and additional introduction of fluorine atoms in position 11 or 12 of the heterocyclic system led to amplification of this activity.
Asunto(s)
Antiinflamatorios/farmacología , Ácidos Carboxílicos/farmacología , Quinazolinas/farmacología , Animales , Antiinflamatorios/química , Diseño de Fármacos , Simulación del Acoplamiento Molecular , Quinazolinas/química , Ratas , Sales (Química) , Relación Estructura-ActividadRESUMEN
The known methods for synthesis of thioxopyrimidines and their condensed analogs with exocyclic sulfur atom are summarized and discussed. The most popular approaches are based on [3+3], [4+2], [5+1] cyclization processes or domino reactions. The literature data analysis shows that the title compounds possess diverse biological activities, such as antioxidant, radioprotective, analgesic, antiinflammatory, antihypertensive, anxiolytic, anamnestic, anticonvulsant, antimicrobial, fungicidal, herbicidal, antiviral, and anticancer.
RESUMEN
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.
Asunto(s)
Antiinflamatorios/síntesis química , Diseño de Fármacos , Quinazolinas/síntesis química , Animales , Antiinflamatorios/farmacología , Espectroscopía de Resonancia Magnética , Simulación del Acoplamiento Molecular , Quinazolinas/química , Quinazolinas/farmacología , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
In this paper the novel N-cycloalkyl-(cycloalkylaryl)-2-[(3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazoline-6-yl)thio]acetamides synthesis by aminolysis of activated by thionyl chloride or carbonyldiimidazole [(3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)-thio]acetic acids and alkylation of the 3-R-6-thio-6,7-dihydro-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones potassium salts with N-cycloalkyl-(cycloalkylaryl)-2-chloroacetamides are proposed. The structures of compounds are determined by (1)H, (13)C NMR, LC-MS and EI-MS analysis. The in vitro anticancer, antibacterial activity and Photobacterium leiognathi Sh1 bioluminescence inhibition of synthesized compounds were revealed. SAR results were discussed. Compound 4.10 was found to be the most anticancer active one, selectively influenced on the non-small cell lung and CNS cancer cell lines, especially on the HOP-92 (log GI(50) = -6.01) and U251 (log GI(50) = -6.00).