7223-38-3Relevant articles and documents
A click chemistry approach to pleuromutilin derivatives, evaluation of anti-MRSA activity and elucidation of binding mode by surface plasmon resonance and molecular docking
Zhang, Zhe,Zhang, Zhao-Sheng,Wang, Xiao,Xi, Gao-Lei,Jin, Zhen,Tang, You-Zhi
, p. 2087 - 2103 (2021/12/02)
Novel series of pleuromutilin analogs containing substituted 1,2,3-triazole moieties were designed, synthesised and assessed for their in vitro antibacterial activity against Methicillin-resistant Staphylococcus aureus (MRSA). Initially, the in vitro antibacterial activities of these derivatives against 4 strains of S. aureus (MRSA ATCC 43300, ATCC 29213, AD3, and 144) were tested by the broth dilution method. Most of the synthesised pleuromutilin analogs displayed potent activities. Among them, compounds 50, 62, and 64 (MIC = 0.5～1 μg/mL) showed the most effective antibacterial activity and their anti-MRSA activity were further studied by the time-killing kinetics approach. Binding mode investigations by surface plasmon resonance (SPR) with 50S ribosome revealed that the selected compounds all showed obvious affinity for 50S ribosome (KD = 2.32 × 10?8～5.10 × 10?5 M). Subsequently, the binding of compounds 50 and 64 to the 50S ribosome was further investigated by molecular modelling. Compound 50 had a superior docking mode with 50S ribosome, and the binding free energy of compound 50 was calculated to be ?12.0 kcal/mol.
Design, synthesis and biological evaluation of novel pleuromutilin derivatives containing piperazine and 1,2,3-triazole linker
Zhang, Guang-Yu,Zhang, Zhe,Li, Kang,Liu, Jie,Li, Bo,Jin, Zhen,Liu, Ya-Hong,Tang, You-Zhi
, (2020/11/02)
A series of novel pleuromutilin derivatives containing piperazine ring, 1, 2, 3-triazoles and secondary amines on the side chain of C14 were synthesized under mild conditions via click reaction. The in vitro antibacterial activities of the synthesized derivatives against four strains of Staphylococcus aureus (MRSA ATCC 43300, ATCC 29213, 144 and AD3) and one strain of Escherichia coli (ATCC 25922) were evaluated by the broth dilution method. Among these derivatives, 22–[2-(4-((4-nitrophenyl piperazine)methyl)-1,2,3-triazol-1-yl)-1-(piperazine-1-yl) ethyl-1-one] deoxy pleuromutilin (compound 59) showed the most prominent in vitro antibacterial effect against MRSA (MIC = 1 μg/mL). Furthermore, compound 59 displayed more rapid bactericidal kinetic than tiamulin time-kill studies and possessed a longer PAE than tiamulin against MRSA in vitro. In addition, in vivo antibacterial activities of compound 59 against MRSA were further evaluated employing thigh infection model. And compound 59 (-8.89 log10 CFU/mL) displayed superior activities than tiamulin. Compound 59 was further evaluated in CYP450 inhibition assay and the results showed that it exhibited low to moderate inhibitory effects on CYP1A2, CYP2E1, CYP2D6 and CYP3A4 enzymes. The PK properties of compound 59 were then measured. The half-life (t1/2), clearance rate (Cl) and the area under the plasma concentration time curve (AUC0→∞) of compound 59 were 0.74 h, 0.29 L/h/kg and 46.28 μg·h/mL, respectively.
Pleuromutilin derivative with 2-aminothiophenol and 1,2,3-triazole side chain, preparation and application
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Paragraph 0121-0123, (2019/11/12)
The invention belongs to the field of medicinal chemistry, and particularly relates to a pleuromutilin derivative with 2-aminothiophenol and a 1,2,3-triazole side chain, preparation and application. The pleuromutilin derivative with 2-aminothiophenol and the 1,2,3-triazole side chain is a compound of a formula 2 or a pharmaceutically acceptable salt of the compound, and a solvent compound, an enantiomer, a diastereomer and a tautomer of the compound of the formula 2 or the pharmaceutically acceptable salt of the compound or a mixture of the compound of the formula 2 or the pharmaceutically acceptable salt of the compound in any ratio, and includes a racemic mixture, and the compound has good inhibition to methicillin-resistant staphylococcus aureus activity, and is especially suitable forbeing used as a novel antibacterial drug for prevention and treatment of infectious diseases caused by human or animals or methicillin-resistant staphylococcus aureus or multi-drug resistant bacteria.(Please see the specification for the formula).
