Oleanolic acid (OA) is a natural cosmeceutical compound with various skin beneficial activities including inhibitory effect on hyaluronidase but the anti-hyaluronidase activity and mechanisms of action of its synthetic analogues remain unclear. Herein, a series of OA derivatives were synthesised and evaluated for their inhibitory effects on hyaluronidase. Compared to OA, an induction of fluorinated (6c) and chlorinated (6g) indole moieties led to enhanced anti-hyaluronidase activity (IC 50 ¼ 80.3 vs. 9.97 and 9.57 mg/mL, respectively). Furthermore, spectroscopic and computational studies revealed that 6c and 6g can bind to hyaluronidase protein and alter its secondary structure leading to reduced enzyme activity. In addition, OA indole derivatives showed feasible skin permeability in a slightly acidic environment (pH ¼ 6.5) and 6c exerted skin protective effect by reducing cellular reactive oxygen species in human skin keratinocytes. Findings from the current study support that OA indole derivatives are potential cosmeceuticals with antihyaluronidase activity.
<b><i>Introduction:</i></b> Cannabinoids including cannabidiol (CBD) have attracted enormous interest as bioactive ingredients for various dermatological and/or cosmeceutical uses. However, topical applications of cannabinoids might be limited without a fundamental understanding of their skin permeability. Herein, we aimed to evaluate the skin permeability of CBD and its topical formulations using artificial skin membrane assays. The solubility and stability of CBD in various surfactants that are commonly used in topical applications were also evaluated. <b><i>Methods:</i></b> CBD and two CBD-incorporated topical formulations (cream and gel) were prepared for this study. Computational predictions (SwissADME and DERMWIN™) and the parallel artificial membrane permeability assay (PAMPA) were used to evaluate the skin permeability of CBD isolate. The Franz cell diffusion (in vitro release testing) assay was used to evaluate the skin permeability of CBD formulations. The solubility and stability of CBD in surfactants were assessed by high-performance liquid chromatography and mass spectrometry analysis. <b><i>Results:</i></b> CBD isolate showed favorable skin permeability in the SwissADME and DERMWIN™ predictions (−Log Kp of 3.6 and 5.7 cm/s, respectively) and PAMPA (−LogPe value of 5.0 at pH of 6.5 and 7.4). In addition, CBD had higher solubility (378.4 μg/mL) in surfactant Tween 20 as compared to its solubility in polyisobutene. In an acidic environment (pH 5 and 6), Tween 20 maintained the CBD content at 81% and 70% over 30 days, respectively. CBD in the formulations of cream and gel also had moderate skin permeability in the Franz cell diffusion assay. <b><i>Conclusion:</i></b> Data from artificial membrane-based assays support that CBD is a skin permeable cannabinoid and the permeability and stability of its formulations may be influenced by several factors such as surfactant and pH environment. Findings from our study suggest that CBD may have suitable skin permeability for the development of dermatological and/or cosmeceutical applications but further studies using in vivo models are warranted to confirm this.
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