Antiaggregant effects of (1, 2, 5‐oxadiazolyl)azasydnone ring assemblies as novel antiplatelet agents. (18th July 2021)

• Record Type: Journal Article
• Authors: Zhilin, Egor S.; Ustyuzhanina, Nadezhda E.; Fershtat, Leonid L.; Nifantiev, Nikolay E.; Makhova, Nina N.
• Is Part Of: Chemical biology & drug design. Volume 100:Number 6(2022)
• Page Start: 1017
• Page End: 1024
• Publication Date: 2021-07-18
• Subjects: antiplatelet activity -- azasydnones -- furoxans -- mechanism of action -- nitrogen heterocycles -- NO‐donors; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.13918
• Languages: English
• ISSNs: 1747-0277

Abstract

Abstract: A series of biheterocyclic assemblies comprising of 1, 2, 5‐oxadiazole and azasydnone scaffolds were synthesized and biologically evaluated as novel nitric oxide (NO)‐donor and antiplatelet agents. Depending on functional substituents at the biheterocyclic core, all studied compounds demonstrated good NO‐donor profiles releasing NO in a wide range of concentrations (19.2%–195.1%) according to a Griess assay. (1, 2, 5‐Oxadiazolyl)azasydnones showed excellent antiplatelet activity in the case of ADP and adrenaline used as inducers completely suppressing the aggregate formation even at the lowest test concentration of 0.0375 μmol/ml, which is a rather unique feature. Moreover, studied biheterocycles possess a selective mechanism of inhibition of platelet aggregation mediated only by ADP and adrenaline, which are considered to be the main inducers causing thrombus formation. In addition, (1, 2, 5‐oxadiazolyl)azasydnones were found to be completely non‐toxic to hybrid endothelial cells EaHy 926. Studies of hydrolytic degradation of the synthesized compounds afforded benzoic acid as a sole detectable decomposition product, which is considered advantageous in drug design. Therefore, (1, 2, 5‐oxadiazolyl)azasydnones represent a novel class of promising drug candidates with improved antiplatelet profile and reduced toxicity enabling their huge potential in medicinal chemistry and drug design. Abstract : A novel series of promising antiplatelet agents based on a (1, 2, 5‐oxadiazolyl)azasydnone core was revealed. Synthesized compounds show high NO‐donor ability, are non‐toxic in vitro and possess a selective mechanism of action. Studies on degradation of (1, 2, 5‐oxadiazolyl)azasydnones afforded benzoic acid as a main decomposition product, which is advantageous in drug design.