Hyaluronidase Inhibitory Activity of Pentacylic Triterpenoids from Prismatomeris tetrandra (Roxb.) K. Schum: Isolation, Synthesis and QSAR Study

Abstract

The mammalian hyaluronidase degrades hyaluronic acid by the cleavage of the β-1,4-glycosidic bond furnishing a tetrasaccharide molecule as the main product which is a highly angiogenic and potent inducer of inflammatory cytokines. Ursolic acid 1, isolated from Prismatomeris tetrandra, was identified as having the potential to develop inhibitors of hyaluronidase. A series of ursolic acid analogues were either synthesized via structure modification of ursolic acid 1 or commercially obtained. The evaluation of the inhibitory activity of these compounds on the hyaluronidase enzyme was conducted. Several structural, topological and quantum chemical descriptors for these compounds were calculated using semi empirical quantum chemical methods. A quantitative structure activity relationship study (QSAR) was performed to correlate these descriptors with the hyaluronidase inhibitory activity. The statistical characteristics provided by the best multi linear model (BML) (R² = 0.9717, R²cv = 0.9506) indicated satisfactory stability and predictive ability of the developed model. The in silico molecular docking study which was used to determine the binding interactions revealed that the ursolic acid analog 22 had a strong affinity towards human hyaluronidase.

Keywords: Prismatomeris tetrandra (Roxb.) K. Schum; QSAR; Rubiaceae; hyaluronidase; molecular docking; semi empirical quantum chemical; ursolic acid.

Figure 1

Synthesis of ursolic acid 1 derivatives with different substituents at C-3. ((C₅H₆N {ClCrNO₃}) = Pyridinium chlorochromate; CH₂Cl₂ = dichloromethane; (CH₃)₂CO = acetone; H₂NOHHCl = hydroxylamine hydrochloride; (CH₃CO)₂ = acetic anhydride; (CH₃SiCH₂N⁺N) = trimethylsilyl diazomethane (TMS)).

Figure 2

Structure activity relationship of pentacyclic triterpenes (PTs).

Figure 3

Comparison of the experimental hyaluronidase activity with the activity presented by the QSAR Equation (1), n = 20, with R² = 0.8579; s² = 0.0246; F = 21.13; four descriptors.

Figure 4

Structure of new PTC A compound.

Figure 5

Superimposed the complex structures of apigenin and 22 with human hyaluronidase (left). The interactions with residues interaction energy below −4 kcal/mol of apigenin (right, top) and 22 (right, bottom) with human hyaluronidase were illustrated. The π–π and hydrogen bonding interaction are depicted in orange and green dashed, respectively.