Synthesis and antibacterial activity of betulonic acid amides with piperazine derivatives

Betulonic acid is obtained via a one-step oxidation of betulin [1, 2] and has reactive functional groups in its structure. It is an available and convenient starting material for synthesizing new biologically active compounds [3–6]. Compounds with antioxidant, anti-inflammatory, antibacterial, hepatoprotective, antiviral, antitumor, and immunostimulant properties have been found among the synthesized derivatives of betulonic acid [4, 7–12]. Compounds with various substituents on C-28, in particular peptides [8] and amides [4, 8, 12], are well-known among them. It is also known that introduction into the triterpenoid acid structure of piperazine groups or its N-substituted derivatives expands the spectrum of their biological activity [4 ,13]. This can be viewed as one of the options for synthesizing new biologically active compounds based on betulonic acid. Herein we present results for the synthesis of amides of betulonic acid with N-derivatives of piperazine and tests of their antibacterial activity. Betulin for the synthesis of betulonic acid was obtained via extraction of Betula platyphylla bark. Its structure was confirmed by comparing PMR and 13C NMR spectra with the literature data [14]. Oxidation of betulin by Jones reagent using the known method [1] produced betulonic acid, the PMR and 13C NMR spectra of which were identical to those published [1, 12]. Betulonic acid chloride (1) was synthesized via reaction with oxalylchloride by the literature method [7]. The structure of 1 was confirmed by comparing its PMR and 13C NMR spectra with the literature data [6]. Amides 2–7 were prepared via reaction of 1 with N-derivatives of piperazine in CH2Cl2 (1:2 mole ratio) in the presence of NEt3 (4 eq). The yields of the target compounds were 74.9–89.8%.