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 transmission-aggregometry 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. Graphical abstract .

Keywords: Acetylsalicylic acid; Antioxidant; Antiplatelet action; Carnosine; Gastrointestinal ulcer; Salicylic acid.

Graphical abstract

.

Fig. 1

Scheme of salicyl-carnosine synthesis. 1 – Acetylsalicylic acid (ASA), 2 – pivaloyl chloride, 3 – salicyl-carnosine (SC); Et3N – trimethylamine, CH3CN – acetonitrile

Fig. 2

Slowdown of nitro blue tetrazolium reduction rate in the xanthine/xanthine oxidase superoxide radical induction system caused by carnosine and salicyl-carnosine (SC) used at concentrations of 2, 4 and 10 mM (* – p < 0.01 compared to carnosine, t-test). N = 10 measurements on each concentration

Fig. 3

Kinetics of SC and carnosine hydrolysis by serum carnosinase during 180 min. N = 6 samples on each time point

Fig. 4

Comparison of Trolox (TR), carnosine (CAR), SC and ASA effects on luminol-enhanced chemiluminescence of leukocytes induced by BaSO4. The data are presented as percentage from control value without tested substances. (* – significant differences with p < 0.05 compared to control, t-test). N (in each group) = 10

Fig. 5

The influence of salicyl-carnosine (SC), acetylsalicylic acid (ASA), carnosine (CAR), ticlopidine (TIC) and Trolox (TR) on ADP-induced platelet aggregation (the data are presented as percentages of the control value without tested substances, M ± SEM); (* – p < 0.05 as compared to control, t-test). N (in each group) = 10

Fig. 6

Effect of carnosine, salicyl-carnosine (SC), and acetylsalicylic acid (ASA) on the healing of acetate ulcers on the anterior wall of the stomach in rats (* – p < 0.05 as compared with control; # – p < 0.05 as compared with carnosine). N (in each group) = 6. Data statistics were analyzed using factorial ANOVA followed by Tukey HSD test