Discovery of novel cannabidiol derivatives with augmented antibacterial agents against methicillin-resistant Staphylococcus aureus.

Drug-resistant bacterium infections are a severe threat to public health and novel antimicrobial agents combating drug-resistant bacteria are an unmet medical need. Although cannabidiol (CBD) has been reported to show antibacterial effects, whether its antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) can be improved remains unclear. Herein, a series of novel CBD derivatives were designed and synthesized using various chemical approaches including amidation, Friedel-Crafts alkylation, and Negishi cross-coupling reaction for the modifications at the C-7, C-2', C-4', and C-6' positions of CBD skeleton. Derivative 21f showed augmented antibacterial activity against MRSA with a minimum inhibitory concentration of 4 µM without cytotoxic effect in microglia BV2 cells. Further mechanistic studies suggested that 21f inhibited the formation of biofilms, induced excess reactive oxygen species, and reduced bacterial metabolism, which collectively led to the acceleration of bacterial death. Findings from this study expand the understanding of CBD derivatives as promising antibacterial agents, which provides useful information for the development of cannabinoid-based antibacterial agents.

Insights into electrochemical oxidation of tris(2-butoxyethyl) phosphate (TBOEP) in aquatic media: Degradation performance, mechanisms and toxicity changes of intermediate products.

Tris (2-butoxyethyl) phosphate (TBOEP) has gained significant attention due to its widespread presence and potential toxicity in the environment. In this study, the degradation of TBOEP in aquatic media was investigated using electrochemical oxidation technology. The anode Ti/SnO2-Sb/La-PbO2 demonstrated effective degradation performance, with a reaction constant (k) of 0.6927 min-1 and energy consumption of 1.24 kW h/m3 at 10 mA/cm2. CV tests, EPR tests, and quenching experiments confirmed that indirect degradation is the main degradation mechanism and ·OH radicals were the predominant reactive species, accounting for up to 93.8%. The presence of various factors, including Cl-, NO3-, HCO3- and humic acid (HA), inhibited the degradation of TBOEP, with the inhibitory effect dependent on the concentrations. A total of 13 intermediates were identified using UPLC-Orbitrap-MS/MS, and subsequent reactions led to their further degradation. Two main degradation pathways involving bond breaking, hydroxylation, and oxidation were proposed. Both Flow cytometry and the ECOSAR predictive model indicated that the intermediates exhibited lower toxic than the parent compound, resulting in a high detoxification rate of 95.9% for TBOEP. Although the impact of TBOEP on the phylum-level microbial community composition was found to be insignificant, substantial alterations in bacterial abundance were noted when examining the genus level. The dominant genus Methylotenera, representing 17.4% in the control group, decreased to 6.9% in the presence of TBOEP and slightly increased to 8.7% in the 4-min exposure group of degradation products. Electrochemical oxidation demonstrated its effectiveness for the degradation and detoxification of TBOEP in aqueous solutions, while it is essential to consider the potential impact of degradation products on sediment microbial communities.

Synthesis and Biological Evaluations of Betulinic Acid Derivatives With Inhibitory Activity on Hyaluronidase and Anti-Inflammatory Effects Against Hyaluronic Acid Fragment Induced Inflammation.

We previously reported that the structural modifications of pentacyclic triterpenoids including oleanolic acid resulted in enhanced hyaluronidase inhibitory activity but whether this applies to other pentacyclic triterpenoids such as betulinic acid (BA) is unknown. Herein, we synthesized BA derivatives with an α,ß-unsaturated ketene moiety and evaluated for their: 1) hyaluronidase inhibitory activity and, 2) anti-inflammatory effects against lipopolysaccharides (LPS) induced inflammation. Compared to BA, the BA derivatives exerted improved anti-hyaluronidase activity (26.3%-72.8% vs. 22.6%) and anti-inflammatory effects by reducing nitrite production in BV2 cells (3.9%-46.8% vs. 3.4%) and RAW264.7 cells (22.7%-49.2% vs. 20.4%). BA derivatives inhibited LPS-induced production of pro-inflammatory cytokines in THP-1 cells (15.2%-22.4%). BA derivatives also exerted promising anti-inflammatory effects against hyaluronic acid fragment induced nitrite production (8.6%-35.6%) in THP-1 cells. BA derivatives showed augmented anti-hyaluronidase and anti-inflammatory effects but further biological evaluations using in vivo models are warranted to confirm their efficacy.

Synthesis and biological evaluations of oleanolic acid indole derivatives as hyaluronidase inhibitors with enhanced skin permeability.

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 (IC50 = 80.3 vs. 9.97 and 9.57 µg/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 = 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 anti-hyaluronidase activity.

Synthesis and biological evaluation of pentacyclic triterpenoid derivatives as potential novel antibacterial agents.

A series of ursolic acid (UA), oleanolic acid (OA) and 18ß-glycyrrhetinic acid (GA) derivatives were synthesized by introducing a range of substituted aromatic side-chains at the C-2 position after the hydroxyl group at C-3 position was oxidized. Their antibacterial activities were evaluated in vitro against a panel of four Staphylococcus spp. The results revealed that the introduction of aromatic side-chains at the C-2 position of GA led to the discovery of potent triterpenoid derivatives for inhibition of both drug sensitive and resistant S. aureus, while the other two series derivatives of UA and OA showed no significant antibacterial activity even at high concentrations. In particular, GA derivative 33 showed good potency against all four Staphylococcus spp. (MIC = 1.25-5 µmol/L) with acceptable pharmacokinetics properties and low cytotoxicity in vitro. Molecular docking was also performed using S. aureus DNA gyrase to rationalize the observed antibacterial activity. This series of GA derivatives has strong potential for the development of a new type of triterpenoid antibacterial agent.