β-Alanilamide of betulonic acid: evaluation of the anti-inflammatory effect in vivo and in silico models
A. A. KHODAKOV1, D. S. BAEV1,2, I. V. SOROKINA1, S. V. AYDAGULOVA1,3, S. A. POPOV1, T. G. TOLSTIKOVA1
1Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
2Boreskov Institute of Catalysis, Siberian Branch of the Russian Academy of Sciences, SRF “SKIF”, Koltsovo, Russia
3Novosibirsk State Medical University, Novosibirsk, Russia
Keywords: β-alanilamide of betulonic acid, inflammation models, mice, molecular targets
Abstract
In the models of the mouse paw acute inflammation induced by various phlogogens (histamine, concanavalin A and sheep erythrocytes), the anti-inflammatory activity of the lupane triterpenoid 3-[3-oxo-20(29)-lupen-28-oil]-aminopropionic acid (β-alanilamide of betulonic acid, ABA) was studied. Experiments were carried out with outbred and inbred (strains СВА, С57BL/6) female mice of reproductive age (body weight 20-30 g). The agent was administered orally in the doses of 50 and 100 mg/kg in the form of a water-Tween suspension one hour before subplantar injection of phlogogen into the paw. Indomethacin substance was used as a reference drug. The predicted values of the energy of ABA binding to key targets in the Nrf2 and NFkB signaling pathways were determined using the molecular docking method. It has been shown that when administered orally in the doses of 50-100 mg/kg, ABA has a moderate anti-inflammatory effect in the models of exudative, B-cell and T-cell inflammation, exhibiting higher activity at low doses. The results of molecular modelling of the possible interaction of ABA with inhibitors of nuclear factors Nrf2 and NFkB (proteins KEAP1 and IKK, respectively) show a greater affinity of ABA for KEAP1 than for IKK. It was found that ABA and betulonic acid have similar probable values of targets binding energy, which suggests common mechanisms of anti-inflammatory action. The current study results and the previous data on the low toxicity and wide range of pleiotropic effects suggest that ABA is a promising chemopreventive agent.
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