A new derivative of acetylsalicylic acid and carnosine: synthesis, physical and chemical properties, biological activity

Abstract

Purpose The aim of this study was to create and assess biological activity of a new compound based on carnosine and acetylsalicylic acid (ASA) that will comprise antioxidant effect with antiplatelet activity, while simultaneously preventing side effects on the gastrointestinal tract. Methods Salicyl-carnosine (SC) was synthesized by condensation of ASA and carnosine. Antioxidant activity was determined by spectrophotometric and chemiluminescence methods. Antiplatelet activity was carried out by the light transmissionaggregometry method using the inductor ADP. Chronic gastric ulcer in rats was modeled using glacial acetic acid. Results Using SOD-like activity, iron-induced chemiluminescence, BaSO4-activated respiratory burst, and evaluation of red blood cell structure stabilization during oxidative damage induced by sodium hypochlorite, it was shown that SC possesses antioxidant activity analogous, or better, than that of carnosine. Antiplatelet activity of SC was evaluated in the blood of healthy individuals, and was also shown to be comparable to, or exceeding that of ASA. Also SC demonstrates high resistance to hydrolysis by tissue and serum carnosinases. Most importantly, it was shown that SC has protected the gastric mucosa against the formation of stomach ulcerative lesions and promoted their epithelization, therefore overcoming the undesirable inherent side effects of ASA. Conclusions SC preserves pharmacologically significant properties of ASA and carnosine while retaining an anti-ulcer activity and resistance to the carnosinase hydrolysis at the same time. These properties are particularly promising for the potential development of new anti-inflammatory and antithrombotic drugs. KeywordsCarnosine . Acetylsalicylic acid . Salicylic acid . Antioxidant . Antiplatelet action . Gastrointestinal ulcer Abbreviations ASA acetylsalicylic acid CL chemiluminescence COX cyclooxygenase HPLC high performance liquid chromatography HRMS high resolution mass spectrometry LP lipoproteins LPO lipid peroxidation NBT nitroblue tetrazolium NSAIDs non-steroidal anti-inflammatory drugs

An overview of the pathogenic mechanisms involved in severe cases of COVID-19 infection, and the proposal of salicyl-carnosine as a potential drug for its treatment

“…Binding carnosine to a different molecule, and thus making it inaccessible to the enzyme, would keep the protective effect while negating its hydrolysis in the human body. This was done successfully by our team ( Kulikova et al, 2020 ). Salicyl-carnosine was synthesized from acetylsalicylic acid and carnosine in accordance with the procedure presented in our published work.…”

“…Patent RU 2694061 C 1]. The description of the synthesis procedure has been previously published ( Kulikova et al, 2020 ). The natural dipeptide carnosine (β-alanyl-L-histidine) is characterized by high antioxidant activity ( Prokopieva et al, 2016 ).…”

“…Salicyl-carnosine was synthesized from acetylsalicylic acid and carnosine in accordance with the procedure presented in our published work. Salicyl-carnosine was not susceptible to hydrolysis over the course of 2 h while incubated in human serum at 37 °C, unlike carnosine, which underwent complete hydrolysis in the same conditions ( Kulikova et al, 2020 ). According to our unpublished data, salicyl-carnosine remains in rat blood in a concentration over 10 μ/ml within 2 h after a single intravenous injection (dosage: 100 μg/ml).…”

“…We propose to investigate salicyl-carnosine as a potential drug for treating COVID-19, due to its anti-oxidative, anti-aggregational, and anti-inflammatory actions, as well as its ability to inhibit erythrocyte hemolysis and lack of detrimental side effects ( Kulikova et al, 2020 ).…”

Carnosine to Combat Novel Coronavirus (nCoV, COVID-19): Molecular Docking and Modeling to Co-Crystallized Host Angiotensin-Converting Enzyme 2 (ACE2) and Viral Spike Protein

“…Salicyl-carnosine is quite similar to the scaffold general structure, although less than carnosine in terms of both bioactivity scores and chemical similarity, however, it is not available for human use (Figure 4, Table 1 and Table 2). Salicylcarnosine present as a better option to bypass the serum carnosinases and hence evade the need for high dose oral carnosine [32]. Carnosine and salicyl-carnosine resemble the scaffold general structure and has quite matching figures.…”