Synthesis of biologically active arginine derivatives derived from salicylamide

Peptidomimetics represent a promising class of biologically active compounds with broad therapeutic potential.¹ In general, peptidomimetics mimic the function of natural peptides in the human body while overcoming their limitations, such as low stability or poor bioavailability, thereby finding application in the treatment of various diseases.^2,3 This study focuses on the synthesis of peptidomimetics derived from salicylic acid and arginine. Salicylic acid–based peptidomimetics have previously been synthesized by the Imramovsky research group and demonstrated both anticancer and antimicrobial activity.^4–7 Peptidomimetics incorporating an arginine moiety exhibit a wide range of biological effects, including antimicrobial⁸, antiviral⁹, antifungal¹⁰, anticancer (e.g., cilengitide)¹¹, and activity against cardiovascular (e.g., argatroban)¹² and neurodegenerative diseases^13,14. In this study, peptidomimetic compounds containing both a salicylic acid derivative and an arginine moiety were designed and synthesized. The synthetic route was based on the construction of the main peptidomimetic backbone via Steglich amidation¹⁵ and the side chain functionalization of arginine through ornithine guanidylation¹⁶. In total, 14 original compounds were synthesized throughout the synthetic route, including intermediates, key ornithine intermediates, and final peptidomimetics. The synthetic route consisted of 7 to 8 steps depending on the form of the final compound – dihydrochloride or (bis)trifluoroacetate. Specifically, 6 arginine-based peptidomimetics (7, 8, 9) and 2 key ornithine intermediates were obtained (5). The final compounds were fully characterized by means of ¹H NMR, ¹³C NMR, ¹⁹F NMR, HRMS, and elemental analysis. In conclusion, the proposed synthetic route was repeatedly verified, and the target compounds were successfully prepared in a quality suitable for biological testing.