Antidiabetic and antiobesity potential of oleanolic acid derivatives

Abstract

The pervasiveness of nontransmissible diseases like Diabetic Mellitus (DM) and obesity has risen rapidly, causing a universal significant public health problem. Undesirable side effects of the current anti-diabetic and anti-obesity drugs have amplified the demand for natural productderived therapeutics. Oleanolic acid (3-hydroxyolean-12-en-28-oic acid) is a naturally occurring pentacyclic triterpenoid known to possess anti-diabetic and anti-obesity properties. Hence, the current study was aimed to evaluate the antidiabetic and anti-obesity properties of the semi-synthesized structural analogues of oleanolic acid, including fluorine-substituted compounds. Oleanolic acid was isolated from the methanolic crude extract of roots of Lantana camara, and seven derivatives were synthesized by C3-OH and C28-COOH functional group modifications. The chemical structures of oleanolic acid analogues were characterized by FTIR, 1 H-NMR, 13C-NMR and HRMS spectroscopic methods. In-vitro anti-diabetic and antiobesity properties were assessed by alpha-glucosidase inhibition and pancreatic lipase, respectively. A significant difference in alpha-glucosidase activity was not obtained (p > 0.05) with oxidation of C3-OH (7.72 ± 0.02 mg L⁻¹) compared to oleanolic acid (28.60 ± 0.84 mg L1 ). In contrast, the highest significant decrease in alpha-glucosidase activity (p < 0.05) was obtained with esterification of C28-COOH (232.32 ± 5.49 mg L⁻¹), esterification of C28-COOH followed by oxidation of C3-OH (173.92 ± 14.26 mg L⁻¹), oxidation of C3-OH followed by fluorination of C28-COOH ( 166.63 ± 9.10 mg L⁻¹) and acetylation of C3-OH followed by fluorination of C28-COOH ( 83.47 ± 4.65 mg L⁻¹) compared to oleanolic acid (28.60 ± 0.84 mg L-1). All seven semi-synthesized derivatives indicate a significant improvement in pancreatic lipase activity (p < 0.05) when compared to oleanolic acid (112.70 ± 6.85 mg L⁻¹), with the highest activity (14.04 ± 1.51 mg L⁻¹) resulted in C3 oxidation followed by fluorination of C28- COOH. The results obtained from the present anti-diabetic study indicated that the modifications at C28-COOH decrease the anti-diabetic potential. The oxidation, esterification and fluorination of C3-OH and esterification and fluorination of C28- COOH showed improved anti-obesity properties. Hence, the current study will be further extended to evaluate the in vivo anti-diabetic and anti-obesity properties.