Novel Inhibitors of Staphyloxanthin Virulence Factor in Comparison with Linezolid and Vancomycin versus Methicillin-Resistant, Linezolid-Resistant, and Vancomycin-Intermediate Staphylococcus aureus Infections in Vivo

Abstract

Our previous work ( Wang et al. J. Med. Chem. 2016 , 59 , 4831 - 4848 ) revealed that effective benzocycloalkane-derived staphyloxanthin inhibitors against methicillin-resistant Staphylococcus aureus (S. aureus) infections were accompanied by poor water solubility and high hERG inhibition and dosages (preadministration). In this study, 92 chroman and coumaran derivatives as novel inhibitors have been addressed for overcoming deficiencies above. Derivatives 69 and 105 displayed excellent pigment inhibitory activities and low hERG inhibition, along with improvement of solubility by salt type selection. The broad and significantly potent antibacterial spectra of 69 and 105 were displayed first with normal administration in the livers and hearts in mice against pigmented S. aureus Newman, Mu50 (vancomycin-intermediate S. aureus), and NRS271 (linezolid-resistant S. aureus), compared with linezolid and vancomycin. In summary, both 69 and 105 have the potential to be developed as good antibacterial candidates targeting virulence factors.

Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate

“…Spectral data of 1 is consistent with those reported in the literature. (Ni et al, 2017) To a stirred solution of 4-vinlypridine (53 mg, 0.5 mmol), 1 (74 mg, 0.3 mmol), P(o-tol) 3 (30 mg, 20 mol%) and triethylamine (0.40 mL, 2.9 mmol) in degassed CH 3 CN (5 mL) under argon was added Pd(OAc) 2 (11 mg, 10 mol%) quickly. The resulting mixture was stirred at 100 °C for 12 h. The mixture was then diluted with water (20 mL) and aqueous phase was extracted with ethyl acetate (15 mL × 3).…”

Targeting virulence factors as an antimicrobial approach: Pigment inhibitors

“…Linezolid (LZD) and VAN were introduced for the first time as positive control drugs into a murine model of S. aureus abscess formation to evaluate the efficacy of our new compounds, thereby comparing our compounds with the last‐resort antimicrobial agents. First, we kept the benzocycloalkane derivatives due to their efficient inhibition in vivo and suggested that inserting a hydrophilic oxygen into the cycloalkane moiety could solve the problem of poor water solubility of the benzocycloalkane skeleton and maintain its potency with limited changes . Moreover, considering that cyclohexane‐derived compound 37 (Figure A) exhibited more significant pigment inhibitory activity than cycloheptane‐derived compound 36 but was limited by its poor water solubility, we chose 37 as a lead compound for further modification.…”

“…First, we kept the benzocycloalkane derivatives due to their efficient inhibition in vivo and suggested that inserting a hydrophilic oxygen into the cycloalkane moiety could solve the problem of poor water solubility of the benzocycloalkane skeleton and maintain its potency with limited changes. 92 Moreover, considering that cyclohexane-derived compound 37 ( Figure 13A) exhibited more significant pigment inhibitory activity than cycloheptane-derived compound 36 but was limited by its poor water solubility, we chose 37 as a lead compound for further modification. Then, the novel skeleton derivative 38 ( Figure 13A) was quickly synthesized by replacing the benzocycloalkane with a chroman segment, which exhibited excellent pigment inhibitory activity (IC 50 = 4.6 ± 0.2 nM) and improved water solubility (13.2 mg/mL, approximately 20-fold increase).…”

para‐Selective Palladium‐Catalyzed C−H Difluoroalkylation by Weak Oxazolidinone Assistance

“…The oxazolidinone heterocycle is a very important structural motif in a variety of pharmaceutically relevant compounds [1] (Figure 1). For instance, Linezolid and Radezolid exhibit potent activity against gram‐positive bacterial including penicillin‐resistant Streptococcus pneumoniae (PRSP), methicillin‐resistant Staphylococcus aureus (MRSA) and vancomycin‐resistant Enterococci (VRE), and are extensively utilized in clinical medicine [2] . In addition, toloxatone exhibits reversible inhibition of monoamine oxidase A, and compound IV is an agonist of metabotropic glutamate receptor (mGluRs), known targets for the treatment of depression and schizophrenia [3] .…”